Phosphonic acid derivatives as inhibitors of protein tyrosine phosphatase 1B (PTP-1B)

ABSTRACT

The invention encompasses the novel class of compounds represented by formula I, which are inhibitors of the PTP-1B enzyme.  
                 
 
     The invention also encompasses pharmaceutical compositions and methods of treating or preventing PTP-1B mediated diseases, including diabetes, obesity, and conditions related to diabetes.

BACKGROUND OF THE INVENTION

[0001] This invention relates to a novel class of phosphonic acidderivatives that are inhibitors of PTP-1B.

[0002] Protein tyrosine phosphatases are a large family of transmembraneor intracellular enzymes that dephosphorylate substrates involved in avariety of regulatory processes (Fischer et al., 1991, Science253:401-406). Protein tyrosine phosphatase-1B (PTP-1B) is a ˜50 kdintracellular protein present in abundant amounts in various humantissues (Charbonneau et al., 1989, Proc. Natl. Acad. Sci. USA86:5252-5256; Goldstein, 1993, Receptor 3:1-15).

[0003] Determining which proteins are substrates of PTP-1B has been ofconsiderable interest. One substrate which has aroused especial interestis the insulin receptor. The binding of insulin to its receptor resultsin autophosphorylation of the receptor, most notably on tyrosines 1146,1150, and 1151 in the kinase catalytic domain (White & Kahn, 1994, J.Biol. Chem. 269:1-4). This causes activation of the insulin receptortyrosine kinase, which phosphorylates the various insulin receptorsubstrate (IRS) proteins that propagate the insulin signaling eventfurther downstream to mediate insulin's various biological effects.

[0004] Seely et al., 1996, Diabetes 45:1379-1385 (“Seely”) studied therelationship of PTP-1B and the insulin receptor in vitro. Seelyconstructed a glutathione S-transferase (GST) fusion protein of PTP-1Bthat had a point mutation in the PTP-1B catalytic domain. Althoughcatalytically inactive, this fusion protein was able to bind to theinsulin receptor, as demonstrated by its ability to precipitate theinsulin receptor from purified receptor preparations and from whole celllysates derived from cells expressing the insulin receptor.

[0005] Ahmad et al., 1995, J. Biol. Chem. 270:20503-20508 used osmoticloading to introduce PTP-1B neutralizing antibodies into rat KRC-7hepatoma cells. The presence of the antibody in the cells resulted in anincrease of 42% and 38%, respectively, in insulin stimulated DNAsynthesis and phosphatidyinositol 3′ kinase activity. Insulin receptorautophosphorylation and insulin receptor substrate-1 tyrosinephosphorylation were increased 2.2 and 2.0-fold, respectively, in theantibody-loaded cells. The antibody-loaded cells also showed a 57%increase in insulin stimulated insulin receptor kinase activity towardexogenous peptide substrates.

[0006] Recently, Kennedy et al., 1999, Science 283: 1544-1548 showedthat protein tyrosine phosphatase PTP-1B is a negative regulator of theinsulin signalling pathway, suggesting that inhibitors of this enzymemay be beneficial in the treatment of Type 2 diabetes. Mice lackingPTP-1B are resistant to both diabetes and obesity.

[0007] Thus, inhibitors of PTP-1B improve insulin-sensitivity. They haveutility in controlling or treating Type 1 and Type 2 diabetes, inimproving glucose tolerance, and in improving insulin sensitivity inpatients in need thereof. The compounds may also be useful in treatingor preventing cancer, neurodegenerative diseases and the like.

SUMMARY OF THE INVENTION

[0008] Compounds represented by Formula I, and pharmaceuticallyacceptable salts thereof, and prodrugs thereof, are PTP-1B inhibitorsand are useful in the treatment of diabetes, obesity and relatedconditions.

[0009] In the compounds having Formula I, R¹ and R² are selected fromthe group consisting of:

[0010] C₁₋₁₀alkyl(R^(a))₀₋₇, C₂₋₁₀alkenyl(R^(a))₀₋₇, Aryl(R^(a))₀₋₃ andHet(R^(a))₀₋₃;

[0011] wherein, each R^(a) independently represents a member selectedfrom the group consisting of: Aryl, OH, CN, halogen, CO₂H, CO₂C₁₋₆alkyl,OC₁₋₆alkyl, C₁₋₆alkyl, OC₁₋₁₀alkyleneCO₂H, O Aryl, C₀₋₆alkyleneSO₃H,C₀₋₆alkyleneCO₂H, C₀₋₆alkyleneCO₂C₁₋₆alkyl, C₀₋₆alkyleneCO₂C₂₋₆alkenyl,C₀₋₆alkyleneC(O)C₁₋₆alkyl, C(O)NR_(3′)R_(4′), NR_(3′)R_(4′),C₁₋₆haloalkyl, OC₁₋₆haloalkyl, S(O)_(Y)C₁₋₆alkyl, S(O)_(y)NR^(3′)R^(4′),and Het, wherein y is 0, 1, or 2, wherein Het, Aryl, alkyl, and alkenylin R^(a) are optionally substituted with 1-3 substituents independentlyselected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, CO₂H, CO₂C₁₋₆alkyl,OC₁₋₁₀alkyl, OH, Het and Aryl, where said Het and Aryl are optionallysubstituted with 1-2 substituents independently selected from halogen,C₁₋₃alkyl, OC₁₋₃alkyl, CF₃, and OCF₃;

[0012] Aryl is a 6-14 membered carbocyclic aromatic ring systemcomprising 1-3 phenyl rings, wherein said rings are fused together sothat adjacent rings share a common side when there is more than onearomatic ring;

[0013] Het represents a 5-10 membered aromatic ring system comprisingone ring or two fused rings, 1-4 heteroatoms, 0-4 of which are N atomsand 0-2 of which are O or S(O)_(y) wherein y is 0-2, and 0-2 carbonylgroups;

[0014] Y, Z¹ and Z² each independently represent—(CR³R⁴)_(a)—X—(CR³R⁴)_(b)— wherein a and b are either 0 or 1, such thatthe sum of a and b equals 0, 1 or 2;

[0015] X represents a bond, O, S(O)_(y), NR^(3′), C(O), OC(O), C(O)O,C(O)NR^(3′), NR^(3′)C(O) or —CH═CH—, where y is as previously defined;

[0016] R³ and R⁴ are independently H, halo, C₁₋₃alkyl, or C₁₋₃haloalkyl;

[0017] each R^(3′) is independently selected from the group consistingof: H, C₁₋₆alkyl, C₁₋₆haloalkyl, OH, C(O)C₁₋₆alkyl, C(O)Aryl, C(O)Het,C(O)C₁₋₆haloalkyl, Aryl and Het;

[0018] each R^(4′) is independently selected from the group consistingof: H, C₁₋₆alkyl, C₁₋₆haloalkyl, Aryl and Het; and

[0019] each W¹ is independently selected from the group consisting of:H, OH, CN, halogen, OC₁₋₆alkyl(R^(a))₀₋₃, S(O)_(y)C₁₋₆alkyl(R^(a))₀₋₃,with y equal to 0-2, S(O)₃H, C₁₋₆alkyl(R^(a))₀₋₃,C₁₋₆haloalkyl(R^(a))₀₋₃, CO₂H, CO₂C₁₋₆alkyl(R^(a))₀₋₃,CO₂C₁₋₆haloalkyl(R^(a))₀₋₃, CO₂C₂₋₆ alkenyl(R^(a))₀₋₃,C(O)C₁₋₆alkyl(R^(a))₀₋₃, C(O)NR³′R^(4′), S(O)_(y) NR^(3′)R^(4′),NR^(3′)R^(4′), Aryl and Het, wherein R^(3′) and R^(4′) are as definedabove, and wherein Aryl and Het may be unsubstituted or are optionallysubstituted with 1-3 substituents independently selected from the groupconsisting of halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, CO₂H, CO₂C₁₋₆alkyl,OC₁₋₆alkyl, OC₁₋₆haloalkyl, and OH; or the two W¹ groups are on adjacentpositions of the aromatic ring and are taken in combination to representa fused phenyl ring.

[0020] Methods of treating, controlling and preventing diabetes,obesity, and other related diseases and conditions using the compoundsof Formula I are taught herein. Pharmaceutical compositions andcombination therapies are also disclosed herein.

DETAILED DESCRIPTION OF THE INVENTION

[0021] In a subset of compounds of Formula I, each W¹ represents H orhalogen. In a preferred subset of these compounds, one W¹ grouprepresents H and the other W¹ group represents a halogen in the positionadjacent to —CF₂P(O)(OH)₂ on the aromatic ring.

[0022] In a subset of any of the groups of compounds above, each Het isselected from the group consisting of pyridinyl,1H-1,2,3-benzotriazolyl, 1,2,4-oxadiazolyl and 1,3-thiazolyl.

[0023] In one embodiment of this invention, Y is —CH₂—.

[0024] In another embodiment of compounds in accordance with claim 1, Z¹and Z² are each independently selected from the group consisting of CH₂,—C(O)—, and a direct bond.

[0025] Another embodiment comprises compounds in which R¹ and R² areeach independently selected from the group consisting of Aryl(R^(a))₀₋₃and Het(R^(a))₀₋₃.

[0026] In another embodiment, R¹ and R² of Formula I are eachindependently selected from the group consisting of

[0027] (a) (CH₂)₀₋₃phenyl, which is optionally mono, di-, ortrisubstituted, wherein the substituents are selected from the groupconsisting of:

[0028] (1) halo,

[0029] (2) C₁₋₆alkoxy,

[0030] (3) C

[0031]1-6alkylthio,

[0032] (4) C₁₋₆alkyl,

[0033] (5) C₁₋₆fluoroalkyl,

[0034] (6) —CO₂H,

[0035] (7) —CO₂—C₁₋₄alkyl,

[0036] (8) —CO₂C₁₋₄fluoroalkyl,

[0037] (9) heteroaryl, which is optionally mono, di-, or trisubstituted,wherein the substituents are independently selected from the groupconsisting of halogen, C₁₋₆alkoxy, C₁₋₆alkylthio, C₁-C₆fluoroalkyl,C₁₋₆alkyl, —CO₂H, —CO₂C₁₋₄alkyl, —CO₂C₁₋₄fluoroalkyl, phenyl, andheteroaryl, wherein the phenyl and heteroaryl are optionally substitutedwith 1-2 groups independently selected from the groups listed in(a)(1)-(a)(8) of this paragraph, and

[0038] (10) phenyl, which is optionally substituted with 1-2substituents independently selected from the group consisting ofhalogen, C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkyl, C₁₋₆fluoroalkyl, —CO₂H,—CO₂C₁₋₄alkyl, —CO₂C₁₋₄fluoroalkyl, phenyl and heteroaryl, wherein thephenyl and heteroaryl are optionally substituted with 1-2 groupsindependently selected from the groups listed in (a)(1)-(a)(8) of thisparagraph, and

[0039] (b) heteroaryl, which is optionally mono-, di- ortri-substituted, wherein the substituents are independently selectedfrom the group consisting of:

[0040] (1) halo,

[0041] (2) C₁₋₆alkoxy,

[0042] (3) C₁₋₆alkylthio,

[0043] (4) C1-6fluoroalkyl,

[0044] (5) C₁₋₆alkyl,

[0045] (6) —CO₂H,

[0046] (7) —CO₂—C₁₋₄alkyl,

[0047] (8) —CO₂C₁₋₄fluoroalkyl,

[0048] (9) phenyl, which is optionally substituted with 1-2 substituentsindependently selected from the group consisting of halogen, C₁₋₆alkoxy,C₁₋₆alkylthio, C₁₋₆alkyl, C₁₋₆fluoroalkyl, CO₂H, —CO₂C₁₋₄alkyl,—CO₂C₁₋₄fluoroalkyl, phenyl and heteroaryl, wherein the phenyl andheteroaryl are optionally substituted with 1-2 groups independentlyselected from the groups listed in (a)(1)-(a)(8) of this paragraph, and

[0049] (10) heteroaryl, which is optionally substituted with 1-2substituents independently selected from the group consisting ofhalogen, C₁₋₆alkoxy, C₁₆alkylthio, C₁₋₆-alkyl, C₁₋₆fluoroalkyl, phenyland heteroaryl, wherein the phenyl and heteroaryl are optionallysubstituted with 1-2 groups independently selected from the groupslisted in (a)(1)-(a)(8) of this paragraph,

[0050] wherein each W¹ is independently selected from the groupconsisting of: halogen, C₁₋₆alkyl, and C₁₋₆fluoroalkyl;

[0051] Y is —CH₂—; and

[0052] Z¹, and Z² are independently selected from the group consistingof CH₂, CH₂CH₂, C(O), C(O)CH₂, CH₂C(O)—, —OC(O)—, C(O)O, and a directbond.

[0053] In another subset of compounds,

[0054] R¹ and R² are each independently selected from the groupconsisting of —(CH₂)phenyl, phenyl, 1,2,4-oxadiazolyl, pyridinyl, and1H-1,2,3-benzotriazolyl, each of which is optionally substituted with1-3 substituents independently selected from halogen, C₁₋₃alkyl, CF₃,phenyl and 1,2,4-oxadiazolyl, wherein phenyl and 1,2,4-oxadiazolyl areoptionally substituted with 1-3 substituents independently selected fromC₁₋₃alkyl, CF₃, phenyl, and 1,2,4-oxadiazolyl,

[0055] Z¹ and Z² are each CO, —OC(O)—, —C(O)O—, or a direct bond,

[0056] Y is CH₂, and

[0057] each W¹ is independently selected from the group consisting ofhydrogen, halogen, and C₁₋₃alkyl, and is in a position on the aromaticring adjacent to the —CF₂P(O)(OH)₂ group.

[0058] Finally, specific embodiments of compounds of Formula I areprovided in Table 1, Table 2 , and/or the compounds exemplified inExamples 1- 24, which are named below:

[0059] Example 1:[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methylphosphonicacid;

[0060] Example 2:Difluoro(4-(3-oxo-2,3-diphenylpropyl)phenyl]methylphosphonic acid;

[0061] Example 3:4-[2-(Benzyloxy)-1-(methoxycarbonyl)-2-oxoethyl]phenyl(difluoro)methylphosphonic acid;

[0062] Example 4: 2-Bromo-4-[2-phenyl-2-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl]phenyl (difluoro)methylphosphonic acid;

[0063] Example 5: 2-Bromo-4-[2-phenyl-2-(5-phenyl-1,2,4-oxadiazol-3-yl)ethyl]phenyl (difluoro)methylphosphonic acid;

[0064] Example 6:[4-(2-Benzotriazol-1-yl-2-m-tolylethyl)-phenyl]difluoromethylphosphonicacid;

[0065] Example 7:{4-[2-Benzotriazol-1-yl-2-(4-fluorophenyl)-ethyl]-2-bromophenyl}difluoromethyl phosphonic acid;

[0066] Example 8:{4-[2-Benzotriazol-1-yl-2-(4-trifluoromethylphenyl)-ethyl]phenyl}difluoromethylphosphonicacid disodium salt;

[0067] Example 9:(4-2-(1H-1,2,3-Benzotriazol-1-yl)-2-[4-(methyloxycarbonyl)phenyl]ethylphenyl)(difluoro)methylphosphonicacid;

[0068] Example 10:{4-[2-(1H-1,2,3-benzotriazol-1-yl)-2-(4-fluorophenyl)ethyl]phenyl }(difluoro)methylphosphonic acid;

[0069] Example 11:{4-[2-(1H-1,2,3-benzotriazol-1-yl)-2-phenylethyl]phenyl}(difluoro)methylphosphonic acid;

[0070] Example 12: {[(2,2-dimethylpropanoyl)oxy]methyl}hydrogen[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methylphosphonate;

[0071] Example 13: Bis{[(2,2-dimethylpropanoyl)oxy]methyl}[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methylphosphonate;

[0072] Example 14:1-{[[[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl)(difluoro)methyl](hydroxy)phosphoryl]oxy}-2-methylpropylpropionate;

[0073] Example 15:[1-(isobutyryloxy)ethyl]hydrogen[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methylphosphonate;

[0074] Example 16:Bis[(isobutyryloxy)methyl][2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methylphosphonate;

[0075] Example 17: [(isobutyryloxy)methyl]hydrogen[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methylphosphonate;

[0076] Example 18:Bis{[(isopropoxycarbonyl)oxy]methyl}[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methylphosphonate;

[0077] Example 19: [(isopropoxycarbonyl)oxy]methyl hydrogen[2-bromo-4-(3-oxo-2,3-diphenyl)phenyl](difluoro)methylphosphate;

[0078] Example 20:Dibenzyl[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methylphosphonate;

[0079] Example 21: Benzyl hydrogen[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methylphosphonate;

[0080] Example 22:[2-bromo-4-(3-oxo-2-phenylbutyl)phenyl](difluoro)methylphosphonic acid;

[0081] Example 23:{2-bromo-4-[3-oxo-2-phenyl-3-(1,3-thiazol-2-yl)propyl]phenyl}(difluoro)methylphosphonic acid; and

[0082] Example 24:{2-bromo-4-[2-(4-methoxy-1,3-thiazol-2-yl)-3-oxo-3-phenylpropyl)phenyl}(difluoro)methylphosphonic acid.

[0083] Methods of treating, preventing, or controlling diabetes andother diseases using the compounds of Formula I are disclosed herein. Amethod of treating, controlling or preventing diabetes and complicationsthereof in a mammalian patient in need of such treatment includes theadministration to the patient an anti-diabetic effective amount of acompound of Formula I. A method of treating, controlling or preventingobesity in a mammalian patient in need of such treatment comprises theadministration to the patient of an anti-obesity effective amount of acompound in accordance with claim 1. Such methods also include theadministration of a second compound, which may be an anti-diabeticcompound, an anti-obesity compound, or an HMG-CoA reductase inhibitor,in an amount effective to treat, control or prevent diabetes or obesity,or to improve a poor lipid profile.

[0084] A method of treating, controlling or preventing atherosclerosisin a mammalian patient in need of such treatment comprises administeringto the patient an effective amount of a compound of Formula I and aneffective amount of an HMG-CoA reductase inhibitor.

[0085] More generally, compounds of Formula I may be used as the activecompound in a method for treating, preventing, or controlling one ormore diseases or conditions selected from Type 1 diabetes, Type 2diabetes, inadequate glucose tolerance, insulin resistance, obesity,hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDLlevels, atherosclerosis, vascular restenosis, inflammatory boweldisease, pancreatitis, adipose cell tumors, adipose cell carcinoma,liposarcoma, dyslipidemia, cancer, and neurodegenerative disease. Themethod comprises the administration of an effective amount of thecompound of Formula I. Combination treatments can also be used in whichcase, the method comprises the administration of a compound of Formula Iand an effective amount of one or more pharmaceutically active compoundsselected from the group consisting of an HMG-CoA reductase inhibitor, ananti-obesity agent, and an antidiabetic compound.

[0086] Pharmaceutical compositions also can be made using the compoundsof Formula I. Compositions that are suitable for the treatment,prevention or control of one or more diseases or conditions selectedfrom Type 1 diabetes, Type 2 diabetes, inadequate glucose tolerance,insulin resistance, obesity, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, low HDL levels, atherosclerosis, vascularrestenosis, inflammatory bowel disease, pancreatitis, adipose celltumors, adipose cell carcinoma, liposarcoma, dyslipidemia, cancer, andneurodegenerative disease contain an effective amount of a compound ofFormula I in combination with a pharmaceutically acceptable carrier.

[0087] Such pharmaceutical compositions may also include a secondanti-diabetic agent or an anti-obesity agent. They may also include acholesterol lowering agent. Pharmaceutical compositions may thereforeinclude: (1) an effective amount of a compound of Formula I, (2) aneffective amount of one or more pharmaceutically active compoundsselected from the group consisting of an HMG-CoA reductase inhibitor, ananti-obesity agent, and an anti-diabetic agent, and (3) apharmaceutically acceptable carrier.

[0088] Such pharmaceutical compositions that contain a second activecompound or composition and that are suitable for the treatment,prevention or control of one or more diseases or conditions selectedfrom the group consisting of Type 1 diabetes, Type 2 diabetes,inadequate glucose tolerance, insulin resistance, obesity,hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDLlevels, atherosclerosis, vascular restenosis, inflammatory boweldisease, pancreatitis, adipose cell tumors, adipose cell carcinoma,liposarcoma, dyslipidemia, cancer, and neurodegenerative disease, may becomprised of the following:

[0089] (1) an effective amount of a compound of Formula 1;

[0090] (2) an effective amount of one or more pharmaceutically activecompounds listed below; and

[0091] (3) a pharmaceutically acceptable carrier; where thepharmaceutically active compounds are selected from the group consistingof:

[0092] (a) insulin sensitizers including (i) PPARγ agonists such as theglitazones (e.g. troglitazone, pioglitazone, englitazone, MCC-555,rosiglitazone, and the like), and compounds disclosed in WO97/27857,97/28115, 97/28137 and 97/27847; (ii) biguanides such as metformin andphenformin;

[0093] (b) insulin or insulin mimetics;

[0094] (c) sulfonylureas such as tolbutamide and glipizide, or relatedmaterials;

[0095] (d) α-glucosidase inhibitors (such as acarbose);

[0096] (e) cholesterol lowering agents such as (i) HMG-CoA reductaseinhibitors (lovastatin, simvastatin and pravastatin, fluvastatin,atorvastatin, rivastatin and other statins), (ii) sequestrants(cholestyramine, colestipol and dialkylaminoalkyl derivatives of across-linked dextran), (iii) nicotinyl alcohol, nicotinic acid or a saltthereof, (iv) PPARα agonists such as fenofibric acid derivatives(gemfibrozil, clofibrate, fenofibrate and benzafibrate), (v) inhibitorsof cholesterol absorption for example beta-sitosterol and (acylCoA:cholesterol acyltransferase) inhibitors for example melinamide and(vi) probucol;

[0097] (f) PPARα/γ agonists;

[0098] (g) antiobesity compounds such as appetite suppressants,fenfluramine, dexfenfluramine, phentiramine, sulbitramine, orlistat,neuropeptide Y5 inhibitors (NP Y5 receptor antagonosts), leptin, whichis a peptidic hormone, β₃ adrenergic receptor agonists, and PPARγantagonists and partial agonists;

[0099] (h) ileal bile acid transporter inhibitors; and

[0100] (i) insulin receptor activators.

Abbreviations

[0101] The following abbreviations have the indicated meanings:

[0102] Ac=acetyl

[0103] AIBN=2.2-azobisisobutyronitrile

[0104] Bn=benzyl

[0105] Bz=benzoyl

[0106] DIBAL=diisobutyl aluminum hydride

[0107] DAST=diethylamino sulfur trifluoride

[0108] DBU=diazabicyclo[5.4.0]undec-7-ene

[0109] DMAP=4-(dimethylamino)pyridine

[0110] DMF=N,N-dimethylformamide

[0111] DMSO=dimethyl sulfoxide

[0112] Et₃N=triethylamine

[0113] HBSS=Hanks balanced salt solution

[0114] HEPES=N¹-[2-Hydroxyethyl]piperazine-N⁴-[2-ethanesulfonic acid]

[0115] KHMDS=potassium hexamethyldisilazide

[0116] KOtBu=potassium tert-butoxide

[0117] LHMDS=lithium hexamethyldisilazide

[0118] LDA=lithium diisopropylamide

[0119] LPS=lipopolysaccharide

[0120] mCPBA=metachloro perbenzoic acid

[0121] MMPP=magnesium monoperoxyphthalate

[0122] Ms=methanesulfonyl=mesyl

[0123] Ms0=methanesulfonate=mesylate

[0124] NBS=N-bromosuccinimide

[0125] nBuLi=n-butyl lithium

[0126] tBuLi=t-butyl lithium

[0127] NCS=N-chlorosuccinimide

[0128] NIS=N-iodosuccinimide

[0129] Oxone®=potassium peroxymonosulfate

[0130] PTP=protein tyrosine phosphatase

[0131] r.t.=room temperature

[0132] rac.=racemic

[0133] Tf=trifluoromethanesulfonyl=triflyl

[0134] TFA=trifluoroacetic acid

[0135] TFAA=trifluoroacetic anhydride

[0136] TfO=trifluoromethanesulfonate=triflate

[0137] THF=tetrahydrofuran

[0138] TLC=thin layer chromatography

[0139] Ts=p-toluenesulfonyl=tosyl

[0140] TsO=p-toluenesulfonate=tosylate

[0141] Tz=1H (or 2H)-tetrazol-5-yl

Alkyl Group Abbreviations

[0142] Me=methyl

[0143] Et=ethyl

[0144] n-Pr=normal propyl

[0145] i-Pr=isopropyl

[0146] n-Bu=normal butyl

[0147] i-Bu=isobutyl

[0148] s-Bu=secondary butyl

[0149] t-Bu=tertiary butyl

[0150] c-Pr=cyclopropyl

[0151] c-Bu=cyclobutyl

[0152] c-Pen=cyclopentyl

[0153] c-Hex=cyclohexyl

Dose Abbreviations

[0154] bid=bis in die=twice daily

[0155] qid=quater in die=four times a day

[0156] tid=ter in die=three times a day

[0157] Alkyl means linear, branched and cyclic structures, andcombinations thereof, containing the indicated number of carbon atoms.Examples of alkyl groups include methyl, ethyl, propyl, isopropyl,butyl, s- and t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, undecyl,dodecyl, tridecyl, tetradecyl, pentadecyl, eicosyl,3,7-diethyl-2,2-dimethyl-4-propylnonyl, cyclopropyl, cyclopentyl,cycloheptyl, adamantyl, cyclododecylmethyl,2-ethyl-1-bicyclo[4.4.0]decyl and the like.

[0158] Fluoroalkyl means alkyl groups of the indicated number of carbonatoms in which one or more hydrogens is replaced by fluorine. Examplesare —CF₃, —CH₂CH₂F, —CH₂CF₃, c-Pr-F₅, c-Hex-F₁₁ and the like. Haloalkylhas the analogous meaning for replacement of one or more hydrogen atomswith any halogen (Cl, Br, F, and/or I).

[0159] Alkenyl means linear, branched and cyclic structures, andcombinations thereof containing a double bond with the indicated numberof carbon atoms. Examples of alkenyl groups include allyl, 2-butenyl,3-butenyl,2-pentenyl, 2-cyclopentenyl, 3-cyclopentenyl,2-methyl-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl and the like.Alkadienyl means the diunsaturated counterpart to alkenyl.

[0160] Alkynyl means linear, branched and cyclic structures, andcombinations thereof containing a triple bond with the indicated numberof carbon atoms. Examples of alkynyl groups include propargyl,2-butynyl, 3-butynyl, 2-pentynyl, cyclopropylethynyl, and the like.

[0161] Alkylene, alkenylene, alkynylene, fluoroalkylene, alkadienylene,and the like, where the suffix “ene” has been added to the name of themonovalent radicals alkyl, alkenyl, alkynyl, fluoroalkyl, alkadienyl,and the like, describe divalent radicals that are the same as theirmonovalent counterparts, except that two hydrogen atoms rather than oneare removed so that the radical will have two attachments.

[0162] Aryl means a 6-14 membered carbocyclic aromatic ring systemcomprising 1-3 phenyl rings. If two or more aromatic rings are present,then the rings are fused together, so that adjacent rings share a commonside.

[0163] Heteroaryl (Het) as used herein represents a 5-10 memberedaromatic ring system containing one ring or two fused rings, 1-4heteroatoms, 0-4 of which are N atoms and 0-2 of which are O or S(O)_(y)wherein y is as previously defined, and 0-2 carbonyl groups. Carbonylgroups, when present, are not counted as heteroatoms. Het includes, butis not limited to, furanyl, diazinyl, imidazolyl, isooxazolyl,isothiazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyridyl, pyrrolyl,tetrazinyl, thiazolyl, thienyl, triazinyl, triazolyl,1H-pyrrole-2,5-dionyl, 2-pyrone, 4-pyrone, pyrrolopyridine, furopyridineand thienopyridine.

[0164] Benzoheteroaryl, which is a subset of Het includes aromatic ringsystems containing one or more heteroatoms which also have a fused6-membered benzene ring, such as 2H-1-benzopyran-2-one,4H-1-benzopyran-4-one, 2(3H)benzofuranone, 3(2H)benzofuranone,2,3-dihydrobenzofuran, 2,3-dihydrobenzothiophene, indole, benzofuran,benzothiophene, benzimidazole, benzoxazole, benzothiazole,benzotriazole, benzothiadiazole, 1H-isoindole-1,3(2H)-dione, quinoline,and isoquinoline.

[0165] Another subset of heteroaryls includes 5-membered heteroaryls,such as the following:

[0166] When a heteroaromatic ring is specified as optionally having oneor more heteroatoms, this means that at least one heteroatom is present,selected from O, S and N, and up to 4 such heteroatoms may be present,depending upon the size of the ring specified.

[0167] When a moiety is specified as being optionally substituted, thenthe same moiety may also remain unsubstituted, unless otherwise stated.

[0168] Finally, when a list of possible choices is provided for a givenmoiety, and the moiety is used in more than one position in a chemicalformula, the selection of a choice for the moiety in each position isindependent of other selections, unless the definition says otherwise.

Metabolites—Prodrugs

[0169] Metabolites of the compounds of this invention that aretherapeutically active and that are described by formula I also arewithin the scope of the claimed invention, as are prodrugs, which arecompounds that are converted to the claimed compounds or salts of theclaimed compounds after they have been administered to a patient. Anon-limiting example of a prodrug of the phosphonic acids of thisinvention would be a monoester or diester of the phosphonic acid group,where the ester functionality has a structure that makes it easilyhydrolyzed or metabolized after administration to a patient. Examples ofsuch prodrugs are the compounds shown below, where R′═H or a C₁₋₆alkylgroup, and R″═a C₁₋₆alkyl group or —OC₁₋₆alkyl group, where Q is theresidue of the molecule that is attached to the —CF₂PO₃H₂ group informula I. The alkyl groups and alkoxy groups may optionally besubstituted with one or more substituents independently selected from1-5 halogen atoms, a phenyl group, or a mixture of these. The phenylgroup, if present, may optionally be substituted with 1-3 substituentsindependently selected from halogen, —CH₃, —CF₃, —OCH₃ and —OCF₃. Inthese compounds, and in general as defined throughout this application,the alkyl groups and the alkyl portions of Oalkyl groups may be linearor branched and may optionally be cycloalkyl or may include a cycloalkylgroup in their structure. For examples of related prodrug structures,see D. N. Srinivasta et al., Bioorganic Chemistry 12, 118-129 (1984).

[0170] Other ester functionalities that may be used in the monoester ordiester phosphonate prodrugs include phenyl esters and benzyl esters,where the phenyl ester groups have the structure —Ophenyl, and thebenzyl ester groups have the structure —OCHR′phenyl, in which R′ is H orC₁₋₆alkyl, and C₁₋₆alkyl is substituted as described above. In eithercase, phenyl is substituted as described above.

[0171] The prodrugs of this invention may therefore be defined ascompounds having the formula Ia shown below:

[0172] In the compound having Formula Ia, one group G is independentlyselected from H, phenyl, —CHR′phenyl, and —CHR′OC(═O)R″, and one group Gis selected from phenyl, —CHR′phenyl and —CHR′OC(═O)R″, where each groupR′ is H or C₁₋₆alkyl and each group R″ is —C₁₋₆alkyl or —OC₁₋₆alkyl,where C₁₋₆alkyl and the alkyl portion of —OC₁₋₆alkyl may optionally besubstituted with one or more substituents independently selected from1-5 halogen atoms, a phenyl group, or a mixture of these. The phenylgroup in —CHR′phenyl, the phenyl group that is an optional substituenton C₁₋₆alkyl and —OC₁₋₆alkyl, and the phenyl ester group, where G isphenyl, may optionally be substituted with 1-3 groups independentlyselected from halogen, —CH₃, —CF₃, —OCH₃ and —OCF₃. By this definition,the phosphonic acid group is a monoester or diester. In preferredcompounds, the groups G that are not H in diesters are the same becauseof the difficulty of synthesizing different G groups on the samephosphonate.

Optical Isomers—Diastereomers—Geometric Isomers

[0173] Some of the compounds described herein contain one or moreasymmetric centers and may thus give rise to diastereomers andenantiomers, which in turn can be resolved as optical isomers. Thepresent invention includes all such diastereomers and enantiomers,including racemic mixtures and resolved, enantiomerically pure forms,and pharmaceutically acceptable salts thereof. Some of the compoundsdescribed herein contain olefinic double bonds, and unless specifiedotherwise, include both E and Z geometric isomers.

Salts

[0174] The pharmaceutical compositions of the present invention comprisea compound of the current invention as an active ingredient or apharmaceutically acceptable salt, thereof, and may also contain apharmaceutically acceptable carrier and optionally other therapeuticingredients. The term “pharmaceutically acceptable salts” refers tosalts prepared from pharmaceutically acceptable bases includinginorganic bases and organic bases. Salts derived from inorganic basesinclude aluminum, ammonium, calcium, copper, ferric, ferrous, lithium,magnesium, manganic salts, manganous, potassium, sodium, zinc, and thelike. Particularly preferred are the ammonium, calcium, magnesium,potassium, and sodium salts. Salts derived from pharmaceuticallyacceptable organic non-toxic bases include salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion exchange resins, such asarginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like.

[0175] When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable acids, including inorganic andorganic acids. Such acids include acetic, adipic, aspartic,1,5-naphthalenedisulfonic, benzenesulfonic, benzoic, camphorsulfonic,citric, 1,2-ethanedisulfonic, ethanesulfonic,ethylenediaminetetraacetic, fumaric, glucoheptonic, gluconic, glutamic,hydriodic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, 2-naphthalenesulfonic, nitric, oxalic,pamoic, pantothenic, phosphoric, pivalic, propionic, salicylic, stearic,succinic, sulfuric, tartaric, p-toluenesulfonic acid, undecanoic,10-undecenoic, and the like. Particularly preferred are citric,hydrobromic, hydrochloric, maleic, methanesulfonic, phosphoric, sulfuricand tartaric acids.

[0176] It will be understood that in the discussion of methods oftreatment or of specific compounds which follows, references to thecompounds of Formula I and other formulae are meant to include thepharmaceutically acceptable salts.

Utilities

[0177] Inhibitors of PTP-1B improve insulin-sensitivity and thus haveutility in preventing or treating Type 1 and Type 2 diabetes, improvingglucose tolerance and insulin-sensitivity when there isinsulin-resistance, and in treating or preventing obesity, all inmammals that are in need of such treatments or that might benefit fromsuch treatments. The compounds also exhibit a beneficial reduction intriglycerides and lipids. Compounds in the present class of phosphonicacids are advantageous over known phosphonic acids previouslyinvestigated as candidate PTP 1B inhibitors. The compounds of thisinvention show improved pharmacokinetics when compared with knownphosphonates. These compounds are active in intact cell-based assays.

[0178] The PTP-1B inhibitors may also be useful in the treatment,prevention or control of a number of conditions that accompany type 2diabetes, including hyperlipidemia, hypertriglyceridemia,hypercholesterolemia (including beneficially raising low HDL levels),atherosclerosis, vascular restenosis, pancreatitis, adipose cell tumors,adipose cell carcinomas such as liposarcoma, dyslipidemia, inflammatorybowel disease, inflammation in general, and other disorders whereinsulin resistance is a component. Finally, the compounds may be used totreat or prevent cancer, such as prostate cancer, neurodegenerativediseases and the like.

Pharmaceutical Compositions

[0179] For the treatment of any of these PTP-1B-mediated diseases theactive compound may be administered orally, topically, parenterally, byinhalation spray or rectally in dosage units containing conventionalpharmaceutically acceptable carriers. The term parenteral as used hereinincludes subcutaneous, intravenous, intramuscular and intrasternalinjection and infusion techniques. In addition to the treatment ofwarm-blooded animals such as mice, rats, horses, cattle, sheep, dogs,cats, etc., the compounds of the invention are useful for the treatmentof humans.

[0180] The pharmaceutical compositions containing the active ingredientmay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsions, hard or soft capsules, or syrups or elixirs.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavouringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with pharmaceutically acceptableexcipients which are suitable for the manufacture of tablets. Theseexcipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example, magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the technique described in the U.S. Pat. Nos. 4,256,108;4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlrelease.

[0181] Formulations for oral use may also be presented as hard gelatincapsules wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredients is mixed withwater or miscible solvents such as propylene glycol, PEGs and ethanol,or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

[0182] Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethycellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavouring agents, and one or more sweeteningagents, such as sucrose, saccharin or aspartame.

[0183] Oily suspensions may be formulated by suspending the activeingredient in a vegetable oil, for example arachis oil, olive oil,sesame oil or coconut oil, or in mineral oil such as liquid paraffin.The oily suspensions may contain a thickening agent, for examplebeeswax, hard paraffin or cetyl alcohol. Sweetening agents such as thoseset forth above, and flavouring agents may be added to provide apalatable oral preparation. These compositions may be preserved by theaddition of an anti-oxidant such as ascorbic acid.

[0184] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, for example sweetening, flavouring andcoloring agents, may also be present.

[0185] The pharmaceutical compositions of the invention may also be inthe form of an oil-in-water emulsion. The oily phase may be a vegetableoil, for example olive oil or arachis oil, or a mineral oil, for exampleliquid paraffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxy-ethylene sorbitan monooleate. The emulsions may also containsweetening and flavouring agents.

[0186] Syrups and elixirs may be formulated with sweetening agents, forexample glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative and flavouringand coloring agents. The pharmaceutical composition may be in the formof a sterile injectable aqueous or oleagenous suspension. Thissuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents which havebeen mentioned above. The sterile injectable preparation may also be asterile injectable solution or suspension in a parenterally-acceptablediluent or solvent, for example as a solution in 1,3-butanediol.Examples of vehicles and solvents include water, Ringer's solution andisotonic sodium chloride. Cosolvents such as ethanol, propylene glycolor polyethylene glycols may also be used. In addition, sterile, fixedoils are conventionally employed as a solvent or suspending medium. Forthis purpose any bland fixed oil may be employed including syntheticmono- or diglycerides. In addition, fatty acids such as oleic acid finduse in the preparation of injectables.

[0187] The compounds may also be administered in the form ofsuppositories. These compositions can be prepared by mixing the drugwith a suitable non-irritating excipient which is solid at ordinarytemperatures but molten at the body temperature and will thereforerelease the drug. Such materials include cocoa butter and polyethyleneglycols.

[0188] For topical use, creams, ointments, gels, solutions orsuspensions containing the compound are employed. (For purposes of thisapplication, topical application includes mouth washes and gargles.)Topical formulations may include cosolvents, emulsifiers, penetrationenhancers, preservatives,emollients and the like.

[0189] The pharmaceutical composition may also be further comprised of asecond anti-diabetic or anti-obesity effective compound.

Dose Ranges

[0190] Dosage levels on the order of from about 0.01 mg to about 100mg/kg of body weight per day are useful in the treatment of theabove-indicated conditions, or alternatively about 0.5 mg to about 7 gper patient per day. For example, the diseases and conditions describedherein may be effectively treated by the administration of from about0.01 to 50 mg of the compound per kilogram of body weight per day, oralternatively about 0.5 mg to about 3.5 g per patient per day.

[0191] The active ingredient is typically combined with the carrier toproduce a dosage form suitable for the particular patient being treatedand the particular mode of administration. For example, a formulationintended for the oral administration of humans may contain from about0.5 mg to about 5 g of the active agent, compounded with an appropriateand convenient amount of carrier material which may vary from about 5 toabout 95 percent of the total composition. Representative dosage formswill generally contain between from about 1 mg to about 500 mg of anactive ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

[0192] It is understood that the specific dose level for any particularpatient will depend upon a variety of factors including the age, bodyweight, general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination and the severity ofthe particular disease undergoing therapy.

Combinations with Other Drugs

[0193] In further aspects, the invention encompasses pharmaceuticalcompositions for treating PTP-1B mediated diseases as defined abovecomprising an effective amount of the active compound and one or moreother pharmaceutically active compounds, such as anti-diabetic compounds(for example, insulin, sulfonyl ureas, PPAR-alpha and/or -gamma ligands,including ligands that have both PPAR-alpha and -gamma activity),anti-obesity compounds, and compounds that improve the lipid profile ofthe patient.

[0194] Thus, the methods of treatment or prevention described herein mayfurther be comprised of administering to said patient a secondanti-diabetic compound in an amount effective to treat, control, orprevent diabetes, alone or in combination with the PTP-1B inhibitors ofthis invention.

[0195] Similarly, the methods of treatment or prevention describedherein may further be comprised of administering to said patient ananti-obesity compound in an amount effective to treat, control orprevent obesity, alone or in combination with the PTP-1B inhibitors ofthis invention.

[0196] Similarly, the methods of treatment of diabetes may comprise theadministration of a cholesterol biosynthesis inhibitor, particularly anHMG-CoA reductase inhibitor, such as lovastatin, simvastatin,pravastatin, fluvastatin, atorvastatin and rivastatin, in an amounteffective to improve the lipid profile. In combination with a PTP-1Binhibitor, this may be beneficial in treating or preventingatherosclerosis and other conditions that often are associated with Type2 diabetes.

[0197] Examples of other pharmaceutically active compounds that may becombined with a compound of Formula I and administered in combinationwith the PTP-1B inhibitors include, but are not limited to, thefollowing compounds or compositions or groups of compounds orcompositions that are used as anti-diabetes compounds (a, b, c, d, f,and i below), anti-obesity compounds (g below), and /or compounds orcompositions for lipid profile control (e and h below):

[0198] (a) insulin sensitizers including (i) PPARγ agonists such as theglitazones (e.g. troglitazone, pioglitazone, englitazone, MCC-555,rosiglitazone, and the like), and compounds disclosed in WO97/27857,97/28115, 97/28137 and 97/27847; (ii) biguanides such as metformin andphenformin;

[0199] (b) insulin or insulin mimetics;

[0200] (c) sulfonylureas such as tolbutamide and glipizide, or relatedmaterials;

[0201] (d) α-glucosidase inhibitors (such as acarbose);

[0202] (e) cholesterol lowering agents such as (i) HMG-CoA reductaseinhibitors (lovastatin, simvastatin and pravastatin, fluvastatin,atorvastatin, rivastatin and other statins), (ii) sequestrants(cholestyramine, colestipol and a dialkylaminoalkyl derivatives of across-linked dextran), (iii) nicotinyl alcohol, nicotinic acid or a saltthereof, (iv) PPARα agonists such as fenofibric acid derivatives(gemfibrozil, clofibrate, fenofibrate and benzafibrate), (v) inhibitorsof cholesterol absorption such as for example beta-sitosterol and acylCoA:cholesterol acyltransferase inhibitors such as for examplemelinamide, and (vi) probucol;

[0203] (f) PPARα/γ agonists;

[0204] (g) antiobesity compounds such as appetite suppressants,fenfluramine, dexfenfluramine, phentiramine, sulbitramine, orlistat,neuropeptide Y5 inhibitors (NP Y5 receptor antagonosts), leptin, whichis a peptidic hormone, β₃ adrenergic receptor agonists, and PPARγantagonists and partial agonists;

[0205] (h) ileal bile acid transporter inhibitors; and

[0206] (i) insulin receptor activators, such as those disclosed incopending, commonly assigned U.S. application Ser. Nos. 09/095,244 and09/280,602.

[0207] Where a second pharmaceutical is used in addition to an activecompound taught herein, the two pharmaceuticals may be administeredtogether in a single composition, separately at approximately the sametime, or on separate dosing schedules. The important feature is thattheir dosing schedules comprise a treatment plan in which the dosingschedules overlap in time and thus are being followed concurrently.

Methods of Synthesis

[0208] The compounds of the present invention can be prepared accordingto the following methods.

METHOD A

[0209] Toluic acid derivative 1 can be treated with NBS in1,2-dichloroethane with AIBN under light at reflux to give bromide 2.The acid can be reduced with borane in THF to provide the alcohol 3which in turn is oxidized with MnO₂ to afford aldehyde 4. Di-tert-butylphosphite can be deprotonated with a base such as LiN(TMS)₂ and reactedwith aldehyde 4. The resulting alcohol 5 is then oxidized with MnO₂ toprovide ketone 6. The ketone 6 is treated with DAST to afford compound7.

[0210] Method A

METHOD A-1

[0211] The methyl ester of 4-aminobenzoic acid II can be brominated withpyridinium tribromide to give III, which is treated with NaNO₂/HCl andKCN/CuCN to give nitrile IV. DIBAL reduction followed by brominationwith POBr₃, gives VI, which is treated with lithium dialkyl phosphite toafford the phosphonate alcohol VII. Swern oxidation followed byfluorination with DAST provide the desired difluoromethyl phosphonateIX.

[0212] Method A-1

METHOD B

[0213] α-Bromo-p-tolunitrile is reduced with DIBAL to provide aldehyde9. Di-tert-butyl phosphite can be deprotonated with a base such as LHMDSand reacted with aldehyde 9 to provide alcohol 10. Alcohol 10 can beoxidized with MnO₂ to afford ketone 11 which in turn is treated withDAST to give 12.

[0214] Method B

METHOD B-1

[0215] 2-Fluoro-4-methyl aniline A is treated with NaNO₂/HCl followed byKCN/CuCN to give nitrile B which in turn is hydrolyzed to give C.Compound C is converted to D using sequence described in Method A. Thissequence can also be applied to the ortho chloro analog.

[0216] Method B-1

METHOD C

[0217] Deoxybenzoin 13 can be deprotonated with potassium tert-butoxideand treated with compound 7 to give 14 (A similar alkylation can beperformed using compound 12.) The ester is then hydrolyzed with AcOH-H₂Oto give acid 15.

[0218] Method C

METHOD D

[0219] Template 16 is treated with a suitable base such as NaH, KOtBu,LHMDS, KHMDS, LDA, nBuLi, tBuLi or a combination of these, and the anionis alkylated with 17 to provide 18 which is then deprotected with acidto provide the desired compound I.

[0220] Method D

METHOD E

[0221] The disodium phosphonate 19 can be alkylated with a chloroalkylester (Synth. Com. 25(18) 2739 (1995)) or carbonate (Antiviral Chemistry& Chemotherapy 8, 557 (1997)) to give both the mono and diprotectedphosphonates which can be separated by flash chromatography on silicagel. Q is the residue of the molecule that is attached to the —CF₂PO₃H₂group.

[0222] Method E

[0223] METHOD F

[0224] The phosphonic acid 22 can be treated with Cs₂CO₃ and achloroalkyl ester or carbonate in CH₃CN to give a mixture of mono anddiprotected phosphonates which can be separated by flash chromatographyon silica gel. Q is the residue of the molecule that is attached to the—CF₂PO₃H₂ group.

[0225] Method F

METHOD G

[0226] The phosphonic acid 22 can be treated with silvertrifluoroacetate to give the disilver salt 23 which can be treated withan iodoalkyl ester (Eur. J. Phar. Sci. 4, 49 (1996)) or carbonate togive a mixture of the mono and diprotected phosphonates which areseparable by flash chromatography. This method can also be used toobtain the benzyl ester using benzyl bromide as alkylating agent. Q isthe residue of the molecule that is attached to the —CF₂PO₃H₂ group.

[0227] Method G

METHOD H

[0228] Benzonitrile 24 can be treated with hydroxylamine hydrochlorideto give 25. Compound 25 can be treated with phenyl acetic acid to affordcompound 26 which in turn is alkylated with 7 from Method A to provide27. The free acid 28 is obtained by treatment of 27 with an acid.

[0229] Method H

METHOD I

[0230] Benzyl nitrile 29 can be treated with hydroxylamine to give 30.Compound 30 can react with phenylacetic acid to afford 31 which in turncan be alkylated with 7 from Method A and a base to provide 32. The freeacid 33 can be obtained from 32 by acid treatment.

[0231] Method I

TABLE 1 Structures of Examples Example Method

1 A + C

2 B + C

3 B + D

4 A + I + D

5 A + H + D

6 B + D

7 A + D

8 B + D

9 B + D

10 B + D

11 B + D

12 A + C + F

13 A + C + G

14 A + C + F

15 A + C + G

16 A + C + G

17 A + C + G

18 A + C + G

19 A + C + G

20 A + C + G

21 A + C + G

22 A + D

23 A + D

24 A + D

[0232] TABLE 2 Other Structures of the Invention

Assays for Demonstrating Biological Activity

[0233] Activity in the compounds of this application is demonstratedusing the following assays for PTP-1B-inhibiting activity.

Phosphatase Assay Protocol

[0234] Materials:

[0235] EDTA-ethylenediaminetetraacetic acid (Sigma)

[0236] DMH-N,N′-dimethyl-N,N′-bis(mercaptoacetyl)-hydrazine (synthesispublished in J. Org. Chem. 56, pp. 2332-2337, (1991) by R. Singh and G.M. Whitesides and can be substituted with DTT-dithiothreitolBistris-2,2-bis(hydroxymethyl)2,2′,2″-nitrilotriethanol-(Sigma) TritonX-100-octylphenolpoly(ethylene-glycolether) 10 (Pierce)

[0237] Antibody: Anti-glutathione S-transferase rabbit (H and L)fraction (Molecular Probes)

[0238] Enzyme: Human recombinant PTP-1B, containing amino acids 1-320,fused to GST enzyme (glutathione S-transferase) or to FLAG peptidepurified by affinity chromatography (Huyer et al, 1997, J. Biol. Chem.,272, 843-852). Wild type contains active site cysteine(215), whereasmutant contains active site serine(215).

[0239] Tritiated peptide: Bz-NEJJ-CONH₂, Mwt. 808, empirical formula,C₃₂H₃₂T₂O₁₂P₂F₄

[0240] Stock Solutions Stock Solutions (10X) Assay Buffer 500 mM Bistris(Sigma), pH 6.2, MW = 209.2 20 mM EDTA (GIBCO/BRL) Store at 4° C.Prepare fresh daily: Assay Buffer (1X) 50 mM Bistris (room temp.) 2 mMEDTA 5 mM DMH (MW = 208) Enzyme Dilution Buffer (keep on ice) 50 mMBistris 2 mM EDTA 5 mM DMH 20% Glycerol (Sigma) 0.01 mg/ml Triton X-100(Pierce) Antibody Dilution Buffer (keep on ice) 50 mM Bistris 2 mM EDTA

IC₅₀ Binding Assay Protocol

[0241] Compounds (ligands) which potentially inhibit the binding of aradioactive ligand to the specific phosphatase are screened in a 96-wellplate format as follows:

[0242] To each well is added the following solutions @25° C. in thefollowing chronological order:

[0243] 1. 110 μl of assay buffer.

[0244] 2. 10 μl. of 50 nM tritiated BzN-EJJ-CONH₂ in assay buffer (1×)@25° C.

[0245] 3. 10 μl. of testing compound in DMSO at 10 differentconcentrations in serial dilution (final DMSO, about 5% v/v) induplicate @25° C.

[0246] 4. 10 μl. of 3.75 μg/ml purified human recombinant GST-PTP-1B inenzyme dilution buffer.

[0247] 5. The plate is shaken for 2 minutes.

[0248] 6. 10 μl. of 0.3 μg/ml anti-glutathione S-transferase (anti-GST)rabbit IgG (Molecular Probes) diluted in antibody dilution buffer @25°C.

[0249] 7. The plate is shaken for 2 minutes.

[0250] 8. 50 μl. of protein A-PVT SPA beads (Amersham) @25° C.

[0251] 9. The plate is shaken for 5 minutes. The binding signal isquantified on a Microbeta 96-well plate counter.

[0252] 10. The non-specific signal is defined as the enzyme-ligandbinding in the absence of anti-GST antibody.

[0253] 11. 100% binding activity is defined as the enzyme-ligand bindingin the presence of anti-GST antibody, but in the absence of the testingligands with the non-specific binding subtracted.

[0254] 12. Percentage of inhibition is calculated accordingly.

[0255] 13. IC₅₀ value is approximated from the non-linear regression fitwith the 4-parameter/multiple sites equation (described in: “RobustStatistics”, New York, Wiley, by P. J. Huber (1981) and reported in nMunits.

[0256] 14. Test ligands (compounds) with larger than 90% inhibition at10 μM are defined as actives.

Enzyme Assay PTP-1B

[0257] Assay buffer 50 mM Bis-Tris (pH=6.3)

[0258] 2 mM EDTA

[0259] 5 mM N,N′-dimethyl-N,N′-bis(mercaptoacetyl)hydrazine (DMH)

[0260] Substrate 10 mM fluorescein diphosphate (FDP) store at −20□C

[0261] Enzyme dilution buffer 50 mM Bis-Tris (pH=6.3)

[0262] 2 mM EDTA

[0263] 5 mM DMH

[0264] 20 %(v/v) glycerol

[0265] 0.01% Triton X-100

[0266] The assay was carried out at room temperature in 96 well plates.The reaction mixture in 170 μl contained 50 mM Bis-Tris (pH=6.3), 2 mMEDTA, 5 mM N,N′-dimethyl-N,N′bis(mercaptoacetyl)hydrazine (DMH) and 10μM fluorescein diphosphare (FDP). 10 μl of 10 concentrations (serialdilution) of the test compound (inhibitor) dissolved in DMSO or DMSOalone for control was added to each well and the plate was mixed for 2min. The reaction was initiated by adding 20 μl of diluted PTP-1B (50 nMin 50 mM Bis/Tris (pH=6.3), 2 mM EDTA, 5 mM DMH, 20 % glycerol and 0.01%Triton X-100. The phosphatase activity was followed by monitoring theappearance of the fluorescent product fluorescein monophosphate (FMP)continuously for 15-30 min, using the Cytofluor II plate reader(PerSeptive Biosystems Inc.) with excitation of 440 nm (slit width 20nm) and emission at 530 nm (slit width 25 nm). All the assays were doneat least in duplicate. The initial rate of FMP formation is plottedagainst the concentration of inhibitor and the data was fitted to4-parameter equation and the inflection point of the fit is the IC₅₀.

PHARMACOKINETICS IN RATS Per Os Pharmacokinetics in Rats PROCEDURE

[0267] The animals are housed, fed and cared for according to theGuidelines of the Canadian Council on Animal Care.

[0268] Male Sprague Dawley rats (325-375 g) are fasted overnight priorto each PO blood level study.

[0269] The rats are placed in the restrainer one at a time and the boxfirmly secured. The zero blood sample is obtained by nicking a small (1mm or less) piece off the tip of the tail. The tail is then stroked witha firm but gentle motion from the top to the bottom to milk out theblood. Approximately 1 mL of blood is collected into a heparinizedvacutainer tube.

[0270] Compounds are prepared as required, in a standard dosing volumeof 10 mL/kg, and administered orally by passing a 16 gauge, 3″ gavagingneedle into the stomach.

[0271] Subsequent bleeds are taken in the same manner as the zero bleedexcept that there is no need to nick the tail again. The tail is cleanedwith a piece of gauze and milked/stroked as described above into theappropriately labelled tubes.

[0272] Immediately after sampling, blood is centrifuged, separated, putinto clearly marked vials and stored in a freezer until analysed.

[0273] Typical time points for determination of rat blood levels afterPO dosing are:

[0274] 0, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h

[0275] After the 4 hr time point bleed, food is provided to the rats adlibitum. Water is provided at all times during the study.

Vehicles

[0276] The following vehicles may be used in PO rat blood leveldeterminations: PEG 200/300/400: restricted to 2 mL/kg Methocel0.5%-1.0%: 10 mL/kg Tween 80: 10 mL/kg

[0277] Compounds for PO blood levels can be in suspension form. Forbetter dissolution, the solution can be placed in a sonicator forapproximately 5 minutes.

[0278] For analysis, aliquots are diluted with an equal volume ofacetonitrile and centrifuged to remove protein precipitate. Thesupernatant is injected directly onto a C-18 HPLC column with UVdetection. Quantitation is done relative to a clean blood sample spikedwith a known quantity of drug. Bioavailability (F) is assessed bycomparing area under the curve (AUC) i.v. versus p.o.$F = {\frac{{AUC}_{po}}{{AUC}_{iv}} \times \frac{{DOSE}_{iv}}{{DOSE}_{po}} \times 100\quad \%}$

[0279] Clearance rates are calculated from the following relation:${CL} = \frac{{DOSE}_{iv}\left( {{mg}/{kg}} \right)}{{AUC}_{iv}}$

[0280] The units of CL are mL/h·kg (milliliters per hour kilogram)

Intravenous Pharmacokinetics in Rats PROCEDURE

[0281] The animals are housed, fed and cared for according to theGuidelines of the Canadian Council on Animal Care.

[0282] Male Sprague Dawley (325-375 g) rats are placed in plastic shoebox cages with a suspended floor, cage top, water bottle and food.

[0283] The compound is prepared as required, in a standard dosing volumeof 1 mL/kg.

[0284] Rats are bled for the zero blood sample and dosed under CO₂sedation. The rats, one at a time, are placed in a primed CO₂ chamberand taken out as soon as they have lost their righting reflex. The ratis then placed on a restraining board, a nose cone with CO₂ delivery isplaced over the muzzle and the rat restrained to the board withelastics. With the use of forceps and scissors, the jugular vein isexposed and the zero sample taken, followed by a measured dose ofcompound which is injected into the jugular vein. Light digital pressureis applied to the injection site, and the nose cone is removed. The timeis noted. This constitutes the zero time point.

[0285] The 5 min bleed is taken by nicking a piece (1-2 mm) off the tipof the tail. The tail is then stroked with a firm but gentle motion fromthe top of the tail to the bottom to milk the blood out of the tail.Approximately 1 ML of blood is collected into a heparinized collectionvial. Subsequent bleeds are taken in the same fashion, except that thereis no need to nick the tail again. The tail is cleaned with a piece ofgauze and bled, as described above, into the appropriate labelled tubes.

[0286] Typical time points for determination of rat blood levels afterI.V. dosing are either:

[0287] 0, 5 min, 15 min, 30 min, 1 h, 2 h, 6 h or 0, 5 min, 30 min, 1 h,2 h, 4 h, 6 h.

Vehicles

[0288] The following vehicles may be used in IV rat blood leveldeterminations: Dextrose: 1 mL/kg 2-Hydroxypropyl-b-cyclodextrin 1 mL/kgDMSO (dimethylsulfoxide): Restricted to a dose volume of 0.1 mL peranimal PEG 200: Not more than 60% mixed with 40% sterile water - 1 mL/kg

[0289] With Dextrose, either sodium bicarbonate or sodium carbonate canbe added if the solution is cloudy.

[0290] For analysis, aliquots are diluted with an equal volume ofacetonitrile and centrifuged to remove protein precipitate. Thesupernatant is injected directly onto a C-18 HPLC column with UVdetection. Quantitation is done relative to a clean blood sample spikedwith a known quantity of drug. Bioavailability (F) is assessed bycomparing area under the curve (AUC) i.v. versus p.o.$F = {\frac{{AUC}_{po}}{{AUC}_{iv}} \times \frac{{DOSE}_{iv}}{{DOSE}_{po}} \times 100\quad \%}$

[0291] Clearance rates are calculated from the following relation:${CL} = \frac{{DOSE}_{iv}\left( {{mg}/{kg}} \right)}{{AUC}_{iv}}$

[0292] The units of CL are mL/h·kg (milliliters per hour kilogram).

PTP 1B Intact Cell Assay

[0293] This assay is the subject of copending, commonly assigned U.S.Provisional Application No. 60/123,243, filed Mar. 8, 1999, which patentapplication is incorporated herein by reference, and was recentlypublished in Cromlish, Wanda A., Paul Payette and Brian P. Kennedy(1999) Biochem Pharmocol 58: 1539-1546.

Construction of Recombinant Baculovirus Transfer Vectors And InsectCells

[0294] Briefly, using the Bac-to-Bac Baculovirus Expression System(Gibco-BRL, Mississauga, Ontario, Canada) PTP 1B cDNA (obtained from Dr.R. L. Erikson, Harvard University, USA), is cloned into the pFASTBACdonor plasmid engineered to include a FLAG sequence at the 5′ end of thecDNA (PTP1B-FL). The recombinant plasmid is transformed into competentDH10BAC E. Coli cells. Following transposition and antibiotic selection,the recombinant bacmid DNA is isolated from selected E. Coli coloniesand used to transfect sf9 insect cells (Invitrogen, San Diego, Calif.,U.S.A.). The sf9 cells are cultured in spinner flasks at 28° C. inGraces supplemented medium (Gibco-BRL, Mississauga, Ontario, Canada)with 10% heat-inactivated fetal bovine serum (Gibco-BRL) following theprotocol of Summers and Smith (A manual for Methods for BaculovirusVectors and Insect Culture Procedures (Bulletin No. 1555). Texas A & MUniversity, Texas Agricultural Experiment Station, College Station,Tex., 1987).

Intact Cell Assay

[0295] Infected sf9 cells expressing PTP1B-FL and mock infected cells,are harvested at 29 hpi (hours post infection) by gentle centrifugation(Beckman GS-6R) at 460 rpm, (48 g) for 5 min. Cells are washed once inassay buffer (Hanks' solution buffered with 15 mM Hepes, pH 7.4,obtained from Sigma, St. Louis, Mo., U.S.A.) and recentrifuged at 300rpm (21 g) for 10 min. The cells are then gently resuspended in assaybuffer and examined using a hemacytometer for cell density and viabilityby trypan blue exclusion. Assays are performed using a Tomtec Quadra 96pipeting robot, programmed to mix the cells gently after each addition.In 200 μL of assay buffer, 2×10⁵ PTP expressing cells or mock infectedcells are dispensed into each well of 96-well polypropylene plates andpre-incubated either with a test compound or DMSO vehicle (3 μL), for 15min at 37° C. The pre-incubated cells are challenged with a finalconcentration of 10 mM pNPP (p-nitrophenyl phosphate, obtained fromSigma-Aldrich Canada Ltd., Oakville, Ontario) for 15 min, centrifuged at4° C. and the amount of substrate hydrolysis is determinedspectrophotometerically at OD₄₀₅.

Oral Glucose Tolerance Test

[0296] Oral glucose tolerance tests are done on conscious Zucker obesefa/fa rats or obese ob/ob mice (age 12 weeks or older). The animals arefasted for 16-18 hours before use for experiments. A test compound or avehicle is given either intraperitoneally or orally 60 minutes beforeoral administration of a glucose solution at a dose of 2 g/kg bodyweight. Blood glucose levels are measured using a Medisense glucometerfrom tail bled samples taken at different time points before and afteradministration of glucose. A time curve of the blood glucose levels isgenerated and the area-under-the-curve (AUC) for 120 minutes iscalculated (the time of glucose administration being time zero). Percentinhibition is determined using the AUC in the vehicle-control group aszero percent inhibition.

[0297] In separate studies, C57BL/6J mice are fed a high fat (35%) andhigh carbohydrate (36%) diet obtained from Bioserv (Frenchtown, N.J.)for 3 to 4 weeks, at which time the mice gained 50 -100% of the baselinebody weight. Oral glucose tolerance tests are done in the same manner asdescribed above.

EXAMPLES

[0298] The invention is further illustrated by the following examples,which are provided to illustrate the invention and are not to beconstrued as limiting the invention in any manner. In these examples,the following experimental methods and procedures were followed, unlessstated otherwise:

[0299] (i) all operations were carried out at room or ambienttemperature, that is, at a temperature in the range 18-25° C.,

[0300] (ii) evaporation of solvent was carried out using a rotaryevaporator under reduced pressure (600-4000 pascals: 4.5-30 mm. Hg) witha bath temperature of up to 60° C.,

[0301] (iii) the course of reactions was followed by thin layerchromatography (TLC) and reaction times are given for illustration only;

[0302] (iv) melting points are uncorrected and ‘d’ indicatesdecomposition; the melting points given are those obtained for thematerials prepared as described; polymorphism may result in isolation ofmaterials with different melting points in some preparations;

[0303] (v) the structure and purity of all final products were assuredby at least one of the following techniques: TLC, mass spectrometry,nuclear magnetic resonance (NMR) spectrometry or microanalytical data;

[0304] (vi) yields are given for illustration only;

[0305] (vii) when given, NMR data is in the form of delta (δ) values formajor diagnostic protons, given in parts per million (ppm) relative totetramethylsilane (TMS) as internal standard, determined at 300 MHz or400 MHz using the indicated solvent; conventional abbreviations used forsignal shape are: s. singlet; d. doublet; t. triplet; m. multiplet; br.broad; etc.: in addition “Ar” signifies an aromatic signal;

[0306] (viii) chemical symbols have their usual meanings; the followingabbreviations have also been used v (volume), w (weight), b.p. (boilingpoint), m.p. (melting point), L (liter(s)), mL (milliliters), g(gram(s)), mg (milligrams(s)), mol (moles), mmol (millimoles), eq(equivalent(s)).

Example 1[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methylphosphonicacid

[0307] Step 1 2-bromo-4-(bromomethyl)benzoic acid

[0308] 2-Bromo-4-methylbenzoic acid (33.5 g, 156 mmol, 1 eq) andN-Bromosuccinimide (40.7 g, 233 mmol, 1.5 eq) were dissolved inrefluxing 1,2-dichloroethane (600 ml) and a catalytic amount of AIBN wasadded. The mixture was left stirring under a lamp and under nitrogen for1 hour. The solvent was removed and the mixture was partitioned between600 ml of water and 600 ml EtOAc. The organic layer was washed twicewith water (600 ml), washed once with brine (600 ml) and then dried withsodium sulfate. The solvent was removed and the crude mixture wastriturated with 10% EtOAc/Hexane for 2 hours and 23.8 g (52%) of thetitle compound was obtained.

[0309] Step 2 2-bromo-4-(bromomethyl)phenyl)methanol

[0310] The compound of Step 1 (23.8 g, 81 mmol, 1 eq) was dissolved inTHF under nitrogen at 0° C. A 1M borane solution in THF (242 ml, 242mmol, 3 eq) was then added dropwise and the mixture was stirred at r.t.for 1 h. under nitrogen. The solution was cooled in an ice bath and 125ml of methanol was then added slowly. The solvent was removed and themixture partitioned between 400 ml of water and 400 ml of 20% THF/EtOAc.The aqueous layer was washed 3 times with 400 ml of 20% THF/EtOAc andthe combined organic layer was dried with sodium sulfate. The solventwas removed and 19.7 g (87%) of the title compound was obtained.

[0311] Step 3 4-(bromomethyl)-2-bromobenzaldehyde

[0312] The compound of Step 2 (8 g, 29 mmol, 1 eq) was dissolved in 10%EtOH/EtOAc (300 ml) and 5 eq of MnO₂ (12.4 g, 142 mmol) was added everyhour for 6 hours. The mixture was filtered through Celite and solventwas removed. 6.5 g (80%) of the title compound was obtained.

[0313] Step 4 di(tert-butyl)[2-bromo-4-(bromomethyl)phenyl](hydroxy)methylphosphonate

[0314] Di-tert-butyl phosphite (14.8 g, 76.3 mmol, 1.05 eq) wasdissolved in 200 ml THF at −78° C. under nitrogen and 72 ml (1.05 eq) of1.06M Lithium bis(trimethylsilyl)amide in THF was added over 30 min. Themixture was left stirring at −78° C. under nitrogen for 30 min and thenadded to a solution of the compound of Step 3 (20.2 g, 72.7 mmol, 1 eq)in 200 ml THF at −78° C. The solution was warmed to 0° C. and thenpoured into 400 ml of half saturated aqueous ammonium acetate. Thelayers were separated and the aqueous layer was washed with 400 mlisopropyl acetate. The organic layers were combined, dried with sodiumsulfate and the solvent removed. The crude solid was then trituratedwith 15% EtOAc/hexane for 2 hours and 30.4 g (89%) of the title compoundwas obtained.

[0315] Step 5 di-(tert-butyl)-2-bromo-4-(bromomethyl) benzoylphosphonate

[0316] The compound of Step 4 was dissolved in acetone, and MnO₂ (40equiv.) was added. The mixture was stirred vigorously for 2-7 hours,then filtered through Celite. The solvent was removed to provide thetitle compound. Alternatively, the title compound can be prepared bySwern oxidation of the compound of Step 4.

[0317] Step 6 di(tert-butyl)[2-bromo-4-(bromomethyl)phenyl)(difluoro)methylphosphonate

[0318] To di(tert-butyl)-2-bromo-4-(bromomethyl)benzoylphosphonate (8.0g, 17 mmol) was added 2-methyl-2-butene (8.0 mL). To the mixture at 0°C. was added diethylamino sulfur trifluoride (40 mL). After a period of24 h, the reaction mixture was poured into 2.2 L of 1/1ethylacetate-hexane, diisopropylethylamine (90 mL) and saturated NaHCO₃(400 mL) at 0° C. The organic phase was separated, dried over Na₂SO₄,filtered and evaporated. The crude material was purified by flashchromatography (20% ethyl acetate in hexane) over silica gel previouslywashed with 20% ethyl acetate hexane containing 1% of Et₃N to give 5.0 gof the title compound.

[0319]¹H NMR (400 MHz, CDCl₃) δ1.50 (18H, s), 4.40 (2H, s), 7.40 (1H,d), 7.60 (1H, d), 7.65 (1H, d).

[0320] Step 7 di(tert-butyl)[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl)(difluoro)methylphosphonate

[0321] To a solution of deoxybenzoin (0.119 g, 0.607 mmol) in THF (3.3mL) at −78° C., under nitrogen, was added a 1M solution of potassiumtert-butoxide (0.672 mL, 0.672 mmol) followed by the bromide of Step 6(0.300 g, 0.610 mmol). After a few minutes at room temperature, anaqueous solution of NH₄OAc was added to the reaction mixture. To theresulting mixture EtOAc was then added. The organic phase was separated,dried over Na₂SO₄, filtered and evaporated under reduced pressure. Thetitle compound was obtained after purification, by flash chromatography(0.300 g).

[0322] Step 82-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methylphosphonicacid

[0323] The compound of Step 7 (0.300 g) was dissolved in a 4/1 mixtureof HOAc/H₂O. After a period of 18 h at room temperature, the solventswere evaporated under reduced pressure to give the title compound (0.260g).

[0324]¹H NMR (400 MHz, CD₃COD₃) δ3.10 (1H, m), 3.55 (1H, m), 5.25 (1H,m), 7.20-8.05 (13H, m).

Example 2 Difluoro(4-(3-oxo-2,3-diphenylpropyl)phenyl]methylphosphonicacid

[0325] Step 1 4-(bromomethyl)benzaldehyde

[0326] To a THF-toluene (2.4 L -0.24 L) solution of α bromo ptolunitrile (266.4 g, 1.36 mol) maintained at an internal temperaturebelow 0° C. was added DIBAL-H in hexane (1.0 M) (1.49 L, 1.49 mol) overa period of 2 h. After a period of 1.5 h, the reaction mixture wastransferred via canula to a 3N HCl solution (8 L) at 0° C. To theresulting suspension EtOAc (4 L) and THF (0.8 L) were added. Afterstirring, the organic phase was separated and evaporated to give ayellow solid. The solid was stirred, in 20% EtOAc in hexane (1.3 L) for3 hours. After filtration and drying, the title compound was obtained(210 g).

[0327] Step 2 di(tert-butyl)[4-(bromomethyl)phenyl](hydroxy)methylphosphonate

[0328] To a solution of di-t-butylphosphite (125 g, 0.640 mol) in THF (2L) was added LiHMDS (0.607 L, 0.643 mol) at −78° C. The lithium salt wastransferred via canula to a −70° C. solution of the aldehyde of Step 1(122 g, 0.612 mL) in THF (2 L). The resulting reaction mixture waswarmed slowly to 0° C. After a period of 1 h at 0° C., aqueous NH₄OAc(1.2 L) and isopropyl acetate (1 L) were added to the reaction mixture.The organic phase was separated, dried over Na₂SO₄, filtered andevaporated under reduced pressure. To the resulting solid was added 20%EtOAc in hexane (1 L) and the mixture stirred overnight. Afterfiltration, the title compound was obtained as a white solid (184 g).

[0329] Step 3 di(tert-butyl) 4-(bromomethy)benzoylphosphonate

[0330] To the alcohol of Step 2 (184 g, 0.468 mol) in EtOAc (8.4 L) wasadded MnO₂ (407 g, 4.68 mol). After a period of 1 h, the reactionmixture was filtered over celite-silica gel. The solvent was evaporatedand 10% EtOAc in Hexane (0.50 L) was added. The solid was filtered toprovide 137 g of the title compound.

[0331] Step 4 di(tert-butyl)[4-(bromomethyl)phenyl](difluoro)methylphosphonate

[0332] To a toluene (250 mL) solution of 2-methyl-2-butene (17.8 g, 256mmol) at 0° C. was added DAST (206 g, 1.28 mol). The ketone of Step 3(50.0 g, 128 mmol) was then added portionwise. After a period of 18 h atroom temperature, the reaction mixture was transferred dropwise to amixture of saturated NaHCO₃ (1.2 L), EtOAc (1.2 L), and Et₃N (250 mL) at0° C. The organic phase was separated, dried over Na₂SO₄, filtered andevaporated under reduced pressure. The compound was purified over silicagel with 20% EtOAc in hexane to provide 29.5 g of material.

[0333] Step 5di(tert-butyl)difluoro[4-(3-oxo-2,3-diphenylpropyl)phenyl]methylphosphonate

[0334] To a solution of deoxybenzoin (10 g, 51 mmol) anddi(tert-butyl)[4-(bromomethyl)phenyl](difluoro)methylphosphonate (11.5g, 28 mmol) in dry DMF (150 mL) at 0° C. was added the NaH (0.90 g, 30mmol, 80% in oil). The ice bath was removed and the mixture was stirredat r.t. for 1 h. The reaction was then quenched with saturated NH₄Clsolution, and the product was extracted with Et₂O. The organic layer waswashed with H₂O and brine, and was then dried (MgSO₄), filtered, andevaporated. The residue was stirred vigourously with 1:10 EtOAc:hexane(75 mL) for 2 h to give, after filtration, 8.8 g of white solid.

[0335]¹H NMR (acetone, d₆), 1.38 (s, 18H), 3.19-3.17 (m, 1H), 3.53-3.60(m, 1H), 5.15 -5.61 (m, 1H), 7.14 -7.20 (m, 1H), 7.23 -7.29 (m, 2H),7.29 -7.37 (m, 4H), 7.37-7.43 (m, 4H), 7.48 -7.54 (m, 1H), 7.98-8.04 (m,2H).

[0336] Step 6difluoro[4-(3-oxo-2,3-diphenylpropyl)phenyl]methylphosphonic acid

[0337] To a solution of the phosphonate ester from Step 5 (0.16 g, 0.373mmol) in HOAc (4 mL) was added H₂O (1 mL). After stirring overnight atr.t., the solvent was removed under vacuum and the residue wasco-evaporated with toluene 2 times.

[0338]¹H NMR (400 MHz, CD₃COCD₃) δ3.10 (1H, m), 3.60 (1H, m), 5.20 (1H,m), 7.15-8.05 (14H, m).

Example 34-[2-(Benzyloxy)-1-(methoxycarbonyl)-2-oxoethyl]phenyl(difluoro)methylphosphonic acid

[0339] Step 1 1-benzyl 3-methyl 2-4-[(ditert-butoxyphosphoryl)(difluoro)methyl]phenylmalonate

[0340] To a solution of benzyl methyl malonate (0.2 g) in DMF (8 mL),was added sequentially NaH (0.08 g, 60% in mineral oil),di(tert-butyl)[[4-(bromomethyl)phenyl](difluoro)methyl]phosphonate (0.83g), and n-Bu₄NI(0.08 g). The reaction mixture was stirred at roomtemperature for 2.5 h, then quenched with 20 mL of saturated aqueousNH₄Cl solution and extracted with 50 mL of 1:1 hexane/EtOAc. The extractwas dried over Na₂SO₄ and concentrated. The residue was purified bysilica gel chromatography eluted with 2:1 hexane/EtOAc. First eluted wasthe title compound (0.2 g) as an oil, followed by 2,2-di{4-[(di-tert-butoxyphosphoryl)(difluoro)methyl]benzyl}malonic acid,benzyl methyl ester (0.3 g) as an oil.

[0341]¹H NMR (400 MHz, acetone-d₆) δ7.49 (2H, d), 7.25 -7.40 (7H, m),5.17 (1H, d), 5.11 (1H, d), 3.87 (1H, t), 3.64 (3H, s), 3.26 (2H, d),1.44 (18H, s).

[0342] Step 2 4-[2-(Benzyloxy)-1-(methoxycarbonyl)-2-oxoethyl]phenyl(difluoro)methylphosphonic acid

[0343] A solution of 1-benzyl 3-methyl 2-4-[(ditert-butoxyphosphoryl)(difluoro)methyl]phenylmalonate (Example 2, Step 4) (40 mg) in 1 mL ofCH₂Cl₂, 3 mL of TFA and 0.2 mL of water was stirred for 2 h and thenconcentrated. The residue was dissolved in 3.5 mL of water and washedwith 2×5mL of 1:1 hexane/ether and the aqueous solution was lyophilizedto give 35 mg of the title compound as a syrup.

[0344]¹H NMR (400 MHz, methanol-d₄) δ7.52 (2H, d), 7.22-7.40 (7H, m),5.16 (1H, d), 5.12 (2H, d), 3.88 (1H, t), 3.65 (3H, s), 3.25 (2H, d).

Example 4 2-Bromo-4-[2-phenyl-2-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl]phenyl (difluoro)methylphosphonic acid

[0345] Step 1 benzene amidoxime

[0346] A mixture of benzonitrile (5.2 g), hydroxlyamine hydrochloride(4.2 g) in EtOH (100 mL) was treated with 6 mL of aqueous 10 N NaOHsolution. The resulting mixture was stirred overnight at roomtemperature and was then heated at 60° C. for 4 h. After cooling, themixture was filtered and the filtrate was concentrated and co-evaporatedwith 2×100 mL of toluene to provide 8 g of the title compound as a whitesolid.

[0347] Step 2 5-benzyl-3-phenyl-1,2,4-oxadiazole

[0348] To a solution of phenylacetic acid (2.04 g) in 50 mL of DMF wasadded carbonyldiimidazole (2.7 g). The mixture was stirred for 20 minand then benzene amidoxime (2.04 g) was added. The resulting mixture wasstirred for 20 min at r.t. and 18 h at 75 ° C. After cooling, thereaction mixture was poured in to 50 mL of water and extracted with 2×50mL of 1:1 hexane/EtOAc. The extract was dried over MgSO4 and filtered.The filtrate was concentrated and the residue was purified by silica gelchromatography, eluting with 1:5 EtOAc/hexane to give 2 g of the titlecompound as a yellow syrup.

[0349]¹H NMR (400 MHz, acetone-d₆) δ8.05 (2H, m), 7.50-7.58 (3H, m),7.43 (2H, d), 7.37 (2H, t), 7.32 (1H, t), 4.41 (2H, s).

[0350] Step 3 di(tert-butyl)[2-bromo-4-[2-phenyl-2-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl]phenyl(difluoro)methyl]phosphonate

[0351] To a mixture of 5-benzyl-3-phenyl-1,2,4-oxadiazole (0.12 g),18-crown-6 (0.02 g), in THF (5 mL) cooled at −60° C. was added dropwisea solution of KOtBu (0.5 mL, 1 M in THF). After stirring for 5 min, asolution of di(tert-butyl)[[2-bromo-4-(bromomethyl)phenyl](difluoro)methyl]phosphonate (Example 1,Step 6) (0.1 g in 0.7 mL of THF) was added and the resulting mixture wasstirred for another 5 min at −60 ° C. and quenched with 3 mL ofsaturated NH₄Cl and 5 mL of water. The mixture was extracted with 30 mLof 2:1 hexane/EtOAc and the extract was dried over Na₂SO₄ and filtered.The filtrate was concentrated and the residue was purified by silica gelchromatography, eluting with 1:3 EtOAc/hexane containing 2 % Et₃N togive 0.13 g of the title compound as a syrup.

[0352]¹H NMR (400 MHz, acetone-d₆) δ7.65-7.70 (2H, m), 7.50-7.55 (1H,m), 7.35-7.47 (3H, m), 7.30-7.35 (4H, m), 7.22-7.27 (1H, m), 4.76 (1H,t), 3.77 (1H, dd), 3.47 (1H, dd), 1.38 (9H, s), 1.34 (9H, s).

[0353] Step 42-bromo-4-[2-phenyl-2-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl]phenyl(difluoro)methylphosphonicacid

[0354] A solution of the product from Step 4 (0.13 g) in 3 mL of AcOHand 0.2 mL water was left at room temperature for 3 days and theco-evaporated with 3×3 ml of toluene to give 0.095 g of the titlecompound as a white solid.

[0355]¹H NMR (400 MHz, acetone-d₆) δ7.55-7.62 (3H, m), 7.45-7.55 (3H,m), 7.25-7.40 (7H, m), 4.73 (1H, dd), 3.78 (1H, dd), 3.46 (1H, dd).

Example 52-Bromo-4-[2-phenyl-2-(5-phenyl-1,2,4-oxadiazol-3-yl)ethyl]phenyl(difluoro)methylphosphonic acid

[0356] Step 1 benzyl amidoxime

[0357] Starting with benzylnitrile and hydroxyamine hydrochloride, thetitle compound was prepared as a white solid by using the same proceduredescribed in Step 1 of Example 4.

[0358] Step 2 3-benzyl-5-phenyl-1,2,4-oxadiazole

[0359] Starting with benzyl amidoxime and benzoic acid, the titlecompound was prepared as a white solid by using the same proceduredescribed in Step 2 of Example 4.

[0360]¹H NMR (400 MHz, acetone-d₆) δ8.10 (2H, d), 7.68 (1H, m), 7.62(2H, m), 7.38 (2H, m), 7.33 (2H, t), 7.27 (1H, m), 4.17 (2H, s).

[0361] Step 3 di(tert-butyl)[2-bromo-4-[2-phenyl-2-(5-phenyl-1,2,4-oxadiazol-3-yl)ethyl]phenyl(difluoro)methyl]phosphonate

[0362] Starting with 3-benzyl-5-phenyl-1,2,4-oxadiazole anddi(tert-butyl)[[2-bromo-4-(bromomethyl)phenyl](difluoro)methyl]phosphonate,the title compound was prepared as an oil by using the same proceduredescribed in Step 3 of Example 4.

[0363]¹H NMR (400 MHz, acetone-d₆) δ8.11 (2H, d), 7.57-7.70 (4H, m),7.50 (2H, d), 7.45 (1H, d), 7.28-7.40 (3H. m), 7.25 (1H, m), 4.67 (1H,dd), 3.62 (1H, dd), 3.43 (1H, dd), 1.42 (9H, s), 1.38 (9H, s).

[0364] Step 42-bromo-4-[2-phenyl-2-(5-phenyl-1,2,4-oxadiazol-3-yl)ethyl]phenyl(difluoro)methylphosphonicacid

[0365] Starting with di(tert-butyl)[2-bromo-4-[2-phenyl-2-(5-phenyl-1,2,4-oxadiazol-3-yl)ethyl]phenyl(difluoro)methyl]phosphonate,the title compound was prepared as a white solid by using the sameprocedure described in Step 4 of Example 4.

[0366]¹H NMR (400 MHz, acetone-d₆) δ8.12 (2H, d), 7.68 (1H, m),7.57-7.66 (3H, m), 7.47-7.53 (3H, m), 7.30-7.38 (3H, m), 7.25 (1H, m).4.66 (1H, dd), 3.64 (1H, dd), 3.42 (1H, dd).

Example 6[4-(2-Benzotriazol-1-yl-2-m-tolylethyl)-phenyl]difluoromethylphosphonicacid

[0367] Step 1 1-(3-methylbenzyl)-1H-benzotriazole

[0368] To a solution of benzotriazole (3 g) in DMF (38 mL) at r.t. wasadded a solution of 10N NaOH (2.75 mL). After stirring for 25 min.,3-methylbenzyl bromide (3.9 mL) was added. The mixture was furtherstirred for 30 min, diluted with H₂O, and extracted with EtOAc. TheEtOAc extract was washed with brine (2×), water, brine, and was thendried (MgSO₄) and concentrated. The residue was stirred in diethylether/hexane to give the title compound as a white solid.

[0369]¹H NMR (Acetone-d₆) δ8.02 (1H, d), 7.71 (1H, d), 7.49 (1H, m),7.37 (1H, m), 7.24-7.11 (4H, m) 5.92 (2H, s), 2.27 (3H, s).

[0370] Step 2[4-(2-benzotriazol-1-yl-2-m-tolylethyl)-phenyl]difluoromethylphosphonicacid

[0371] A solution of 1-(3-methylbenzyl)-1H-benzotriazole (1 g) in THF(25 mL) at −78° C. was placed under high vacuum for 5 min., then N₂ wasintroduced in the reaction vessel. A solution of 0.98M n-BuLi in hexanes(4.5 mL) was then added, and the solution turned deep blue immediately.After stirring for 5 min at −78° C., a solution of(4-bromomethylphenyl)-difluoromethylphosphonic acid di-tert-butyl ester(Example 2, Step 4) (1.85 g) in THF (3 mL) was added. The deep bluecolor disappeared. The mixture was then stirred at −78° C. for 10 min,then quenched with H₂O and extracted with EtOAc. The EtOAc extract waswashed with brine, dried (MgSO₄) and concentrated. Chromatography oversilica gel and elution with hexane:EtOAc (65:35), followed by stirringin diethyl ether provided 915 mg of the intermediate.

[0372]¹H NMR (Acetone-d₆) δ7.94 (1H, d), 7.76 (1H, d), 7.46 -7.35 (9H,m), 7.30 (1H, t), 7.21 (1H, t), 7.10 (1H, d), 6.42(1H, t), 4.23 (1H, m),4.06 (2H, m), 3.87 (1H, m), 2.28 (3H, s), 1.31 (18H, d).

[0373] Step 3[4-(2-Benzotriazol-1-yl-2-m-tolylethyl)-phenyl]difluoromethy phosphonicacid.

[0374] The product from Step 2 was dissolved in HOAc (6 mL) and water(1.2 mL) and stirred at r.t overnight. After removal of solvents, theresidue was stirred in diethyl ether to give 155 mg (55%) of the titlecompound as a white solid.

[0375]¹H NMR (Acetone-d₆) δ7.90 (1H, d), 7.74 (1H, d), 7.46-7.32 (7H,m), 7.24 (1H, t), 7.11(1H , d),6.47 (1H, m), 4.20 (1H, m), 3.85 (1H,dd), 2.28 (3H, s).

Example 7{4-[2-Benzotriazol-1-yl-2-(4-fluorophenyl)-ethyl]-2-bromophenyl}difluoromethylphosphonic acid

[0376] Step 1 1-(4-fluorobenzyl)-1H-benzotriazole

[0377] To a solution of benzotriazole (12 g) in DMF (150 mL) at r.t. wasadded a solution of 10N NaOH (11 mL). After stirring for 30 min.,4-fluorobenzyl bromide (3.9 mL) was added. The mixture was furtherstirred for 3 hrs, diluted with H₂O, and extracted with EtOAc. The EtOAcextract was washed water (2×), dried (MgSO₄) and concentrated. Theresidue was stirred in diethyl ether/hexane to afford the title compoundas a white solid.

[0378] Step 2{4-[2-benzotriazol-1-yl-2-(4-fluorophenyl)-ethyl]-2-bromophenyl}difluoromethylphosphonicacid.

[0379] A solution of 1-(4-fluorobenzyl)-1H-benzotriazole (91 mg) in THF(5 mL) at −78° C. was pumped under high vacuum for 5 min., then N₂ wasintroduced in the reaction vessel. A solution of 0.98M n-BuLi in hexanes(0.41 mL) was then added, and the solution turned deep blue immediately.After stirring for 5 min at −78° C., a solution of(2-bromo-4-bromomethylphenyl)difluoromethylphosphonic acid di-tert-butylester (Example 1, Step 6)(157 mg) in THF (1.5 mL) was added. The deepblue color disappeared. The mixture was then stirred at −78° C. for 15min then quenched with H₂O and extracted with EtOAc. The EtOAc extractwas washed with brine, dried (MgSO₄) and concentrated. Chromatographyover silica gel and elution with hexane:EtOAc (65:35, 0.2% Et₃N),provided 85 mg of the intermediate.

[0380]¹H NMR (Acetone-d₆) δ7.96 (1H, d), 7.78 (1H, d), 7.71 -7.32(7H,m), 7.13 (2H, t), 6.55 (1H, m), 4.19 (1H, m), 3.89(1H, m), 1.36 (18H,d).

[0381] Step 3{4-[2-Benzotriazol-1-yl-2-(4-fluorophenyl)-ethyl]-2-bromophenyl}difluoromethylphosphonic acid.

[0382] The above intermediate product was dissolved in HOAc (3 mL) andwater (0.6 mL) and stirred at r.t overnight. After removal of solvent,the residue was stirred in diethyl ether to give the title compound as awhite solid.

[0383]¹H NMR (Acetone-d₆) δ7.96 (1H, d), 7.75 (1H, d), 7.68 (1H, s),7.61 (2H, m), 7.46 (2H, m), 7.35 (2H, t), 7.13 (2H, t,), 6.57 (1H, m),4.18 (1H, m), 3.86 (1H, m).

Example 8{4-[2-Benzotriazol-1-yl-2-(4-trifluoromethylphenyl)-ethyl]phenyl}difluoromethylphosphonicacid disodium salt

[0384] Step 1 1-(3-trifluoromethylbenzyl)-1H-benzotriazole

[0385] To a solution of benzotriazole (3 g) in DMF (38 mL) at r.t. wasadded a solution of 10N NaOH (2.75 mL). After stirring for 25 min.,3-trifluoromethylbenzyl bromide (4.39 mL) was added. The mixture wasfurther stirred for 30 min., diluted with H₂O, and extracted with EtOAc.The EtOAc extract was washed brine (2×), water, brine, dried (MgSO₄) andconcentrated. The residue was stirred in diethyl ether/hexane to afford3.96 g of the title compound as a white solid.

[0386] Step 2{4-[2-benzotriazol-1-yl-2-(3-trifluoromethylphenyl)-ethyl]phenyl}difluoromethylphosphonicacid disodium salt.

[0387] A solution of 1-(3-trifluoromethylbenzyl)-1H-benzotriazole (1 g)in THF (25 mL) at −78° C. was placed under high vacuum for 5 min., thenN₂ was introduced in the reaction vessel. A solution of 0.98M n-BuLi inhexanes (3.67 mL) was added, and the solution turned deep blueimmediately. After stirring for 5 min at −78° C., a solution of(4-bromomethylphenyl)difluoromethylphosphonic acid di-tert-butyl ester(Example 2, Step 4) (1.47 g) in THF (5 mL) was added. The deep bluecolor disappeared. The mixture was then stirred at −78° C. for 30 minthen quenched with H₂O and extracted with EtOAc. The EtOAc extract waswashed with brine, dried (MgSO₄) and concentrated. Chromatography oversilica gel and elution with hexane:EtOAc (65:35, 0.2% Et₃N), provided1.9 g of the intermediate.

[0388] Step 3{4-[2-Benzotriazol-1-yl-2-(3-trifluoromethylphenyl)-ethyl]phenyl}difluoromethylphosphonicacid disodium salt.

[0389] The above intermediate product (300 mg) was dissolved in HOAc (10mL) and water (2 mL) and stirred at r.t overnight. After removal ofsolvent, the residue was chromatographed on reverse phase silica gel(C₁₈), using 30 to 50% CH₃CN in water to afford the phosphonic acid (199mg). The phosphonic acid was dissolved in water, sodium hydroxide 1N(0.8 ml) was added and the solution was lyophilized.

[0390] The residue was stirred in ethyl acetate, the suspension wascentrifuged, the supernatant was discarded, more ethyl acetate wasadded. Vigorous mixing, followed by centrifugation and removal of thesupernatant layer afforded the title compound after drying under highvacuum.

[0391]¹H NMR (Acetone-d₆) δ7.93 (1H, d), 7.80 (1H, s), 7.75 (1H, d),7.69 (1H, d), 7.60-7.50(4H, m), 7.46 (1H, t), 7.37 (1H, t), 7.20 (2H,d), 6.47 (1H, dd), 4.12 (1H, m), 3.75 (1H, m).

Example 9(4-2-(1H-1,2,3-Benzotriazol-1-yl)-2-[4-(methyloxycarbonyl)phenyl]ethylphenyl)(difluoro)methylphosphonicacid

[0392] Step 1 methyl 4-(1H-1,2,3-benzotriazol-1-ylmethyl)benzoate

[0393] To a solution of benzotriazole (1.14 g, 9.6 mmol) in DMF (25 mL)at 0° C. was added methyl 4-bromomethylbenzoate (2.22, 9.6 mmol) and NaH(12.25 mmol, 60% in oil). After stirring for 2 h, the mixture wasdiluted with aqueous NH₄Cl, extracted with EtOAc. The EtOAc extract waswashed H₂O (3×), dried (MgSO₄) and concentrated. The residue waschromatographed to give 1.32 g (51%) of the title compound as a whitepowder.

[0394] Step 2 (4-2-(1H-1,2,3-benzotriazol-1-yl)-2-[4-(methyloxycarbonyl)phenyl]ethylphenyl)(difluoro)methylphosphonic acid di-tert-butyl ester

[0395] To a solution of methyl4-(1H-1,2,3-benzotriazol-1-ylmethyl)benzoate (804 mg, 3 mmol) and(4-bromomethylphenyl) difluoromethylphosphonic acid di-tert-butyl ester(Example 2, Step 4) (1.23 g, 3.0 mmol) in THF (20 mL) at −40° C. wasadded a solution of 1.0 M potassium tert-butoxide in THF (3.3 mL, 3.3mmol). After stirring for 1 h at −40° C., aqueous NH₄Cl was added, themixture was extracted with EtOAc. The EtOAc extract was washed withbrine, dried (MgSO₄) and concentrated. The residue was chromatographedto give 894 mg (50%) of the title compound as a white powder.

[0396] Step 3 (4-2-(1H-1-2,3-benzotriazol-1-yl)-2-[4-(methyloxycarbonyl)phenyl]ethylphenyl)(difluoro)methylphosphonic acid

[0397] To a solution of the product obtained from Step 2 (48 mg, 0.079mmol) in HOAc (1 mL) was added H₂O (0.15 mL). The mixture was stirred atr.t. for 20 h. The solvent was evaporated to give the title compound.

[0398]¹H NMR (Acetone-d₆) δ3.83 (s, 3H), 3.86 (m, 1H), 4.20 (m, 1H),6.55 (m, 1H), 7.34 (m, 6H), 7.63 (d, 2H), 7.72 (d, 1H), 7.95 (m, 3H).

Example 10{4-[2-(1H-1,2,3-benzotriazol-1-yl)-2-(4-fluorophenyl)ethyl]phenyl}(difluoro)methylphosphonicacid

[0399] The title compound was prepared as described in Steps 1 and 2 ofExample 8, followed by Step 3 of Example 9.

[0400]¹H NMR (Acetone-d₆) δ7.91 (d, 1H), 7.74 (d, 1H), 7.60 (m, 2H),7.50 -7.30 (m, 6H), 7.11 (t, 2H), 6.52 (dd, 1H), 4.18 (dd, 1H), 3.86(dd, 1H).

Example 11{4-2-(1H-1,2,3-benzotriazol-1-yl)-2-phenylethyl]phenyl}(difluoro)methylphosphonic acid

[0401] The title compound was prepared as described in Steps 1 and 2 ofExample 8, followed by Step 3 of Example 9.

[0402]¹H NMR (Acetone-d₆) δ7.90 (d, 1H), 7.53 (d, 2H), 7.50 -7.25 (m,9H), 6.50 (dd, 1H), 4.20 (dd, 1H), 3.86 (dd, 1H).

Example 12 {[(2,2-dimethylpropanoyl)oxy]methyl}hydrogen[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methylphosphonate

[0403] A mixture of [-2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methyl phosphonic acid (Example 1) (2.00 g, 4.0mmol), chloromethyl pivalate (6.0 mL) and Cs₂CO₃ (2.50 g) in CH₃CN (60mL) was refluxed for 18 h. The reaction mixture was partitioned betweensaturated NH₄Cl and EtOAc. The organic phase was separated, dried overNa₂SO₄ and evaporated underreduced pressure. The title compound waspurified by flash chromatography (1.4 g)

[0404]¹H NMR (400 MHz, acetone d₆) δ1.15 (9H, s), 3.05 (1H, m), 3.50(1H, m), 5.10 (1H, t), 5.45 (2H, AB), 7.15 (13H, m).

Example 13Bis{[(2,2-dimethylpropanoyl)oxy]methyl}[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methylphosphonate

[0405] To disilver [2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro, methylphosphonate (prepared according to theprocedure in Eur. J. of Pharm. Sci. 4, 49-59 (1996)) (2.65 g, 3.71 mmol)in CH₃CN (15 mL) was added iodomethyl pivalate (2.71 g, 11.15 mmol). Thereaction mixture was stirred at room temperature overnight, and was thenevaporated to dryness. The residue was dissolved in dichloromethane andflash chromatography 1.6 g.

[0406]¹H NMR (300 MHz, acetone-d₆) δ8.02 (2H, d), 7.62 (1H, s),7.12-7.52 (10H, m), 5.7 (4H, m), 5.2 (1H, t), 3.52 (1H, m), 3.12 (1H,m), 1.18 (18H, s).

Example 141-{[[[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl)(difluoro)methyl](hydroxy)phosphoryl]oxy}-2-methylpropylpropionate

[0407] Step 1 1-Chloro-2-methylpropyl propionate

[0408] To a flask containing ZnCl₂ (0.57 g) at 0° C. was added dropwisepropionyl chloride (32.0 g) followed by isobutyraldehyde (25.0 g) over30 min. After a period of 2 h at room temperature, saturated NaHCO₃solution was added to the reaction mixture. The mixture was thenextracted with EtOAc, dried over NaSO₄, filtered and evaporated underreduced pressure. The title compound was distilled using a water pumpaspirator

[0409] Step 21-{[[[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl)(difluoro)methyl](hydroxy)phosphoryl]oxy}-2-methylpropylpropionate

[0410] The title compound was prepared as described in Example 12.1 ¹HNMR (400 MHz, acetone-6) δ0.90 to 1.1 (m, 9H), 1.95 (m, 1H), 2.30 (q,2H), 3.05 (m, 1H), 3.50 (m, 1H), 5.05 (m, 1H), 6.40 (m, 1H), 7.15 to8.00 (m, 13H).

Example 15[1-(isobutyryloxy)ethyl]hydrogen[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methylphosphonate

[0411] Step 1 1-chloroethyl-2-methylpropanoate

[0412] The literature procedure (Synth. Comm. 2739 (1995)) was modifiedas follows. To a flask containing dry ZnCl₂ (1.36 g, 10 mmol) under N₂at 0° C. was added 2-methylpropanoyl chloride (52.4 mL, 0.5 mol). Afterstirring for 5 min at 0° C., acetaldehyde (28 mL, 0.5 mol) was addeddropwise over a period of 1 h. The mixture was stirred a further 1.5 h,at which point it was partitioned between Et₂O and saturated NaHCO₃solution. The organic phase was dried (MgSO₄), filtered, and evaporatedto give a brown oil. A portion of this was distilled under wateraspirator vacuum to give a colorless oil bp. 48-50° C.

[0413] Step 2 1-iodoethyl-2-methylpropanoate

[0414] To a solution of the chloro compound from Step 1 (2.6 g, 17.3mmol) in CH₃CN (20 mL) at r.t. was added NaI (2.85 g, 19 mmol). Theflask was covered with Al foil and the reaction was stirred ON at r.t.The orange suspension was filtered and the filtrate was evaporated todryness. The crude product was dissolved in Et₂O/H₂O and the organicphase was washed with aqueous sodium metabisulfite and brine. Afterdrying (MgSO₄), filtering, and removal of solvent, a pale brown oil(1.92 g) was obtained.

[0415] Step 31-{[(2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methyl](hydroxy)phosphoryl]oxy}ethyl2-methylpropanoate

[0416] To a solution of the silver salt from Example 13 (50 mg, 0.07mmol) in CH₃CN (1.0 mL) at r.t. was added 1-iodoethyl-2-methylpropanoate(51 mg, 0.21 mmol). After 2.5 h at r.t. the solvent was evaporated andthe residue was applied directly to a flash column as a suspension inCH₂Cl₂. Elution with 1:10 MeOH:CH₂Cl₂ afforded the title compound as atan colored foam (26 mg). MS−ESI M⁻¹=608.8

Example 16Bis[(isobutyryloxy)methyl][2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methylphosphonate

[0417] Step 1

[0418] To a solution of(2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro) methylphosphonicacid (0.5 g, 9.27 mmol) in ethanol (1 mL) was added a solution of silvertrifluoroacetate (0.4 g, 1.81 mmol) in ethanol (1 mL) at roomtemperature. The reaction mixture was stirred for 1 hour. Then, thesuspension thus obtained was evaporated to dryness. The residue wasco-distilled with toluene followed by acetonitrile, then the solid waspumped under high vacuum overnight.

[0419] Step 2

[0420] To disilver [2-bromo-4-(3-oxo-2,3diphenylpropyl)phenyl](difluoro) methylphosphonate (0.7 g, 9.27 mmol) inacetonitrile (5 mL) was added iodomethyl 2-methylpropanoate (Synth.Comm. 25 (18), 2739-49 1995) at r.t. The reaction mixture was stirredovernight. The mixture was evaporated to dryness and redissolved indichloromethane. Flash chromatography (30% EtOAc/hexane) then gave thetitle compound (0.15 g).

[0421]¹H NMR (300 MHz, acetone-d₆) δ8.02 (2H, d), 7.6 (1H, s), 7.12-7.55(10H, m), 5.6-5.75 (4H, m), 5.22 (1H, t), 3.55 (1H, m), 3.15 (1H, m),2.6 (2H, m), 1.14 (12H,d).

Example 17 [(isobutyryloxy)methyl]hydrogen[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methylphosphonate

[0422] The title compound was obtained from further elution (with 10%MeOH/CH2CL2) of the chromatography of Example 16.

[0423]¹H NMR (300 MHz, acetone-d₆) δ8.02 (2H, d), 7.11-7.62 (11H, m),5.55 (4H, m), 5.19 (1H, m), 3.50 (1H, m), 3.00 (1H, m), 2.40 (2H, m),1.0 (6H, m).

Example 18 Bis{[(isopropoxycarbonyl)oxy]methyl}[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methylphosphonate

[0424] To disilver[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro) methylphosphonate (see Example 13) (0.9 g, 1.7 mmol) in CH₃CN (10 mL) wasadded iodomethyl isopropyl carbonate (Antiviral chemistry andchemotherapy 1997 8(6), 557) at r.t. The reaction mixture was stirredovernight. The reaction mixture was evaporated and redissolved indichloromethane and flash chromatography (30% EtOAc/hexane) gave thetitle compound 0.07 g.

[0425]¹H NMR (300 MHz, acetone-d₆) δ8.0 (2H, d), 7.6 (1H, s), 7.15-7.55(10H, m), 5.72 (4H, m), 5.22 (1H, t), 5.10 (2H, m), 3.55 (1H, m), 3.15(1H, m), 1.30 (12H, d).

Example 19 [(isopropoxycarbonyl)oxy]methyl hydrogen[2-bromo-4-(3-oxo-2,3-diphenyl)phenyl](difluoro)methylphosphate

[0426] From the previous flash chromatography (Example 18), furtherelution with 10% MeOH/CH₂Cl₂ gave the title compound 0.168 g.

[0427]¹H (300 MHz, methanol-d₄) δ7.95 (2H, d), 7.1-7.55 (11H, m), 5.4(2H, d), 5.02 (1H, t), 3.45 (1H, m), 3.02 (1H, m), 1.25 (6H, d).

Example 20Dibenzyl[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methylphosphonate

[0428] To disilver [2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro) methylphosphonate (see Example 13) (0.4g, 0.56 mmol) in CH₃CN (4 mL) was added benzyl bromide 0.33 g, 1.9mmole) at room temperature. The reaction mixture was stirred overnight,and was then evaporated to dryness. The residue was redissolved indichlomethane and flash chromatography (30% EtOAc/hexane) gave the titlecompound 0.09 g.

[0429]¹H NMR(300 MHz, acetone-d₆) δ8.02 (2H, d), 7.6 (1H, s), 7.1-7.52(20H, m), 5.2 (1H, t), 4.95-5.15 (4H, m), 3.52 (1H, m), 3.12 (1H, m).

Example 21 Benzyl hydrogen[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro) methylphosphonate

[0430] Further elution of the flash chromatography of Example 21 with10% MeOH/CH₂Cl₂ afforded the title compound 0.09 g.

[0431]¹H NMR(300 MHz, acetone-d₆) δ7.98 (2H, d), 7.0-7.5 (16H, m),4.98-5.15 (3H, m), 3.35 (1H, m), 2.85 (1H, m).

Example 22[2-bromo-4-(3-oxo-2-phenylbutyl)phenyl](difluoro)methylphosphonic acid

[0432] Step 1 di(tert-butyl)[2-bromo-4-(3-oxo-2-phenylbutyl)phenyl](difluoro)methylphosphonate

[0433] To a degassed solution of 1-phenylacetone (100 mg, 0.75 mmol) anddi(tert-butyl)-2-bromo-4-(bromomethyl)phenyl(difluoro)methyl phosphonate(Example 1 Step 6) (367 mg, 0.75 mmol) in DMF (3 mL) at 0° C. was addedNaH (80% in oil, 25 mg, 0.82 mmol). After 10 min at 0° C., the ice bathwas removed and the reaction was stirred at r.t. for 30 min. Thereaction was quenched with saturated NH₄Oac solution and the product wasextracted with Et₂O. The organic layer was washed with H₂O and brine,and was then dried (MgSO₄), filtered, and evaporated. The residue waspurified by flash chromatography (1:5 followed by 1:2 EtOAc:hexane) togive a colorless oil (230 mg).

[0434] Step 2[2-bromo-4-(3-oxo-2-phenylbutyl)phenyl](difluoro)methylphosphonic acid

[0435] The title compound was prepared from the product of Step 1according to the procedure of Example 1 Step 8.

[0436]¹H NMR (CD₃COCD₃) δ2.00 (3H, s), 2.90-2.97 (1H, m), 3.34-3.52 (1H,m), 4.20-4.26 (1H, m), 7.19-7.24 (1H, m), 7.24-7.30 (3H, m), 7.30-7.36(2H, m), 7.46-7.52 (2H, m).

Example 23{2-bromo-4-[3-oxo-2-phenyl-3-(1,3-thiazol-2-yl)propyl]phenyl}(difluoro)methylphosphonic acid

[0437] Step 1 1,3-thiazol-2-yl[(trimethylsilyl)oxy]acetonitrile

[0438] To a solution of 1,3-thiazole-2-carbaldehyde (1.0 g, 8.8 mmol)and ZnI₂ (10 mg) in CH₂Cl₂ (10 mL) was added TMSCN (1.65 mL, 12.4 mmol).After stirring ON at r.t., the solvent was removed to give the desiredcompound as a syrup (1.9 g).

[0439] Step 2 2-phenyl-1-(1,3-thiazol-2-yl)ethanone

[0440] To a solution of the product from Step 1 (0.4 g, 1.9 mmol) indegassed THF (4 mL) at −78° C. was added LHMDs. After stirring at −78°C. for 15 min, benzyl bromide (0.27 mL, 2.3 mmol) was added, andstirring was continued at −78° C. for 15 min, followed by 1 h at r.t.The reaction was then quenched by the addition of saturated NH₄Clsolution, and the product was extracted with EtOAc. The organic layerwas washed with H₂O and brine, and was then dried (MgSO₄), filtered, andevaporated. The residue was purified by flash chromatography (1:10EtOAc:hexane) to give 0.16 g of the product.

[0441] Step 3 di(tert-butyl){2-bromo-4-[3-oxo-2-phenyl-3-(1,3-thiazol-2-yl)propyl]phenyl}(difluoro)methylphosphonate

[0442] To a degassed solution of the product from Step 2 (0.16 g, 0.79mmol) and di(tert-butyl)[2-bromo-4-(bromomethyl)phenyl](difluoro)methylphosphonate (Example 1,Step 6) (387 mg, 0.79 mmol) in DMF (4 mL) at 0° C. was added NaH (80% inoil, 26 mg, 0.86 mmol). The ice bath was removed and the mixture wasstirred at r.t. for 30 min. Saturated NH₄Oac solution was then added,and the product was extracted with Et₂O. The organic layer was washedwith H₂O and brine, and was then dried (MgSO₄), filtered, andevaporated. After flash chromatography with 1:2 EtOAc: hexane, theproduct was obtained as a beige foam. (0.27 g).

[0443] Step 4{2-bromo-4-[3-oxo-2-phenyl-3-(1,3-thiazol-2-yl)propyl]phenyl}(difluoro)methylphosphonic acid

[0444] The title compound was obtained from the product of Step 2following the procedure described in Example 1 Step 8.

[0445]¹H NMR (CD₃COCD₃) δ3.15-3.26 (1H, m), 3.55-3.66 (1H, m), 5.42-5.50(1H, m) 7.16-7.46 (6H, m), 7.46-7.56 (1H, m), 7.56-7.63 (1H, m),7.97-8.07 (2H, m).

Example 24{2-bromo-4-[2-(4-methoxy-1,3-thiazol-2-yl)-3-oxo-3-phenylpropyl)phenyl}(difluoro)methylphosphonic acid

[0446] Step 1 2-(4-methoxy-1,3-thiazol-2-yl)-1-phenylethanone

[0447] To a suspension of2-(4-hydroxy-1,3-thiazol-2-yl)-1-phenylethan-1-one (0.5 g, 2.3 mmol) inacetone (10 mL) at r.t. was added MeI (0.17 mL, 2.7 mmol), followed byK₂CO₃ (315 mg, 2.3 mmol). After stirring ON at r.t., the solvent wasremoved and the residue was taken up in Et₂O/H₂O. The organic layer wasdried (MgSO₄), filtered, and evaporated to yield o.43 g of the titlecompound.

[0448] Step 2 di(tert-butyl){2-bromo-4-[2-(4-methoxy-1,3-thiazol-2-yl)-3-oxo-3-phenylpropyl]phenyl}(difluoro)methylphosphonate

[0449] To a degassed solution of the product from Step 1 (0.15 g, 0.61mmol) in THF (3 mL) at −78° C. was added KOtBu. After 10 min, a solutionof the product from Example 1 Step 6 (0.3 g, 0.61 mmol) in THf (2 mL)was added. The reaction was stirred at −78° C. for 30 min, followed by30 min at r.t. Saturated NH₄Cl solution was then added, and the productwas extracted with EtOAc. The organic layer was washed with H₂O andbrine, and was then dried (MgSO₄), filtered, and evaporated. Flashchromatography (1:5 followed by 1:2 EtOAc:hexane) gave the product as anorange-colored syrup (45 mg).

[0450] Step 3{2-bromo-4-[2-(4-methoxy-1,3-thiazol-2-yl)-3-oxo-3-phenylpropyl)phenyl}(difluoro) methylphosphonic acid

[0451] The title compound was prepared from the product of Step 2 in thesame manner as described in Example 1 Step 8.

[0452]¹H NMR (CD₃COCD₃) δ3.05-3.15 (1H, m), 3.22 (3H, s), 3.51-3.59 (1H,m), 4.40-4.47 (1H, m), 6.92 (1H, s), 7.43-7.51 (3H, m), 7.51-7.58 (1H,m), 7.62-7.68 (1H, m), 7.68-7.73 (1H, m), 7.98-8.04 (2H, m).

What is claimed is:
 1. A compound represented by formula I:

or a pharmaceutically acceptable salt thereof, wherein: R¹ and R² areselected from the group consisting of: C₁₋₁₀alkyl(R^(a))₀₋₇,C₂₋₁₀alkenyl(R^(a))₀₋₇, Aryl(R^(a))₀₋₃ and Het(R^(a))₀₋₃; wherein, eachR^(a) independently represents a member selected from the groupconsisting of. Aryl, OH, CN, halogen, CO₂H, CO₂C₁₋₆alkyl, OC₁₋₆alkyl,C₁₋₆alkyl, OC₁₋₁₀alkyleneCO₂H, OAryl, C₀₋₆alkyleneSO₃H,C₀₋₆alkyleneCO₂H, C₀₋₆alkyleneCO₂C₁₋₆alkyl, C₀₋₆alkyleneCO₂C₂₋₆alkenyl,C₀₋₆alkyleneC(O)C₁₋₆alkyl, C(O)NR_(3′)R_(4′, NR) _(3′)R_(4′, C)₁₋₆haloalkyl, OC₁₋₆haloalkyl, S(O)_(y)C₁₋₆alkyl, S(O)_(y)NR^(3′)R^(4′),and Het, wherein y is 0, 1, or 2, wherein Het, Aryl, alkyl, and alkenylin R^(a) are optionally substituted with 1-3 substituents independentlyselected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, CO₂H, CO₂C₁₋₆alkyl,OC₁₋₁₀alkyl, OH, Het and Aryl, where said Het and Aryl are optionallysubstituted with 1-2 substituents independently selected from halogen,C₁₋₃alkyl, OC₁₋₃alkyl, CF₃, and OCF₃; Aryl is a 6-14 memberedcarbocyclic aromatic ring system comprising 1-3 phenyl rings, whereinsaid rings are fused together so that adjacent rings share a common sidewhen there is more than one aromatic ring; Het represents a 5-10membered aromatic ring system comprising one ring or two fused rings,1-4 heteroatoms, 0-4 of which are N atoms and 0-2 of which are O orS(O)_(y) wherein y is 0-2, and 0-2 carbonyl groups; y, Z¹ and Z² eachindependently represents —(CR³R⁴)_(a)—X—(CR³R⁴)_(b—)wherein a and b areeither 0 or 1, such that the sum of a and b equals 0, 1 or 2; Xrepresents a bond, O, S(O)_(y), NR^(3′), C(O), OC(O), C(O)O,C(O)NR^(3′), NR^(3′)C(O) or —CH═CH—, where y is as previously defined;R³ and R⁴ are independently H, halo, C₁₋₃alkyl, or C₁₋₃haloalkyl; eachR^(3′) is independently selected from the group consisting of: H,C₁₋₆alkyl, C₁₋₆haloalkyl, OH, C(O)C₁₋₆alkyl, C(O)Aryl, C(O)Het, C(O)C₁₋₆haloalkyl, Aryl and Het; each R^(4′) is independently selected from thegroup consisting of: H, C₁₋₆alkyl, C₁₋₆haloalkyl, Aryl and Het; and eachW¹ is independently selected from the group consisting of: H, OH, CN,halogen, OC₁₋₆alkyl(R^(a))₀₋₃, S(O)_(y)C₁₋₆alkyl(R^(a))₀₋₃, with y equalto 0-2, S(O)₃H, C₁₋₆alkyl(R^(a))₀₋₃, C₁₋₆haloalkyl(R^(a))₀₋₃, CO₂H,CO₂C₁₋₆alkyl(R^(a))₀₋₃, CO₂C₁₋₆haloalkyl(R^(a))₀₋₃,CO₂C₂₋₆alkenyl(R^(a))₀₋₃, C(O)C₁₋₆alkyl(R^(a))₀₋₃, C(O)NR³′R^(4′),S(O)_(y)NR^(3′)R^(4′), NR^(3′)R^(4′), Aryl and Het, wherein R^(3′) andR^(4′) are as defined above, and wherein Aryl and Het may beunsubstituted or are optionally substituted with 1-3 substituentsindependently selected from the group consisting of halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, CO₂H, CO₂C₁₋₆alkyl, OC₁₋₆alkyl, OC₁₋₆haloalkyl, and OH;or the two W¹ groups are on adjacent positions of the aromatic ring andare taken in combination to represent a fused phenyl ring.
 2. A compoundin accordance with claim 1 wherein each W¹ represents H or halogen.
 3. Acompound in accordance with claim 2, wherein one W¹group represents Hand the other W¹ group represents a halogen in the position adjacent to—CF₂P(O)(OH)₂ on the aromatic ring.
 4. A compound in accordance withclaim 1 wherein each Het is selected from the group consisting ofpyridinyl, 1H-1,2,3-benzotriazolyl, 1,2,4-oxadiazolyl and 1,3-thiazolyl.5. A compound in accordance with claim 1 wherein Y is —CH₂—.
 6. Acompound in accordance with claim 1 wherein Z¹ and Z² are eachindependently selected from the group consisting of: CH2, —C(O)—, and adirect bond.
 7. A compound in accordance with claim 1, wherein R¹ and R²are each independently selected from Aryl(R^(a))₀₋₃ and Het(R^(a))₀₋₃.8. A compound having formula I, wherein R₁ and R₂ are each independentlyselected from the group consisting of (a) (CH₂)₀₋₃phenyl, which isoptionally mono, di-, or trisubstituted, wherein the substituents areselected from the group consisting of: (1) halo, (2) C₁₋₆alkoxy, (3)C₁₋₆alkylthio, (4) C₁₋₆alkyl, (5) C₁₋₆fluoroalkyl, (6) —CO₂H, (7)—CO₂—C₁₋₄alkyl, (8) —CO₂C 1-4fluoroalkyl, (9) heteroaryl, which isoptionally mono, di-, or trisubstituted, wherein the substituents areindependently selected from the group consisting of halogen, C₁₋₆alkoxy,C₁₋₆alkylthio, C₁-C₆fluoroalkyl, C₁₋₆alkyl, —CO₂H, —CO₂C₁₋₄alkyl,—CO₂C₁₋₄fluoroalkyl, phenyl, and heteroaryl, wherein the phenyl andheteroaryl are optionally substituted with 1-2 groups independentlyselected from the groups listed in (a)(1)-(a)(8) of this claim, and (10)phenyl, which is optionally substituted with 1-2 substituentsindependently selected from the group consisting of halogen, C₁₋₆alkoxy,C₁₋₆alkylthio, C₁₋₆alkyl, C₁₋₆fluoroalkyl, —CO₂H, —CO₂C₁₋₄alkyl,—CO₂C₁₋₄fluoroalkyl, phenyl and heteroaryl, wherein the phenyl andheteroaryl are optionally substituted with 1-2 groups independentlyselected from the groups listed in (a)(1)-(a)(8) of this claim, and (b)heteroaryl, which is optionally mono-, di- or tri-substituted, whereinthe substituents are independently selected from the group consistingof: (1) halo, (2) C₁₋₆alkoxy, (3) C₁₋₆alkylthio, (4) C1-6fluoroalkyl,(5) C₁₋₆alkyl, (6) —CO₂H, (7) —CO₂—C₁₋₄alkyl, (8) —CO₂C₁₋₄fluoroalkyl,(9) phenyl, which is optionally substituted with 1-2 substituentsindependently selected from the group consisting of halogen, C₁₋₆alkoxy,C₁₋₆alkylthio, C₁₋₆alkyl, C₁₋₆fluoroalkyl, CO₂H, —CO₂C₁₋₄alkyl,—CO₂C₁₋₄fluoroalkyl, phenyl and heteroaryl, wherein the phenyl andheteroaryl are optionally substituted with 1-2 groups independentlyselected from the groups listed in (a)(1)-(a)(8) of this claim, and (10)heteroaryl, which is optionally substituted with 1-2 substituentsindependently selected from the group consisting of halogen, C₁₋₆alkoxy,C₁₋₆alkylthio, C₁₋₆alkyl, C₁₋₆fluoroalkyl, phenyl and heteroaryl,wherein the phenyl and heteroaryl are optionally substituted with 1-2groups independently selected from the groups listed in (a)(1)-(a)(8) ofthis claim, wherein each W¹ is independently selected from the groupconsisting of: halogen, C₁₋₆alkyl, and C₁₋₆fluoroalkyl; Y is —CH₂—; andZ¹, and Z² are independently selected from the group consisting of CH₂,CH₂CH₂, C(O), C(O)CH₂, CH₂C(O)—, —OC(O)—, C(O)O, and a direct bond.
 9. Acompound in accordance with claim 8, wherein R¹ and R² are eachindependently selected from the group consisting of —(CH₂)phenyl,phenyl, 1,2,4-oxadiazolyl, pyridinyl, and 1H-1,2,3-benzotriazolyl, eachof which is optionally substituted with 1-3 substituents independentlyselected from halogen, C₁₋₃alkyl, CF₃, phenyl and 1,2,4-oxadiazolyl,wherein phenyl and 1,2,4-oxadiazolyl are optionally substituted with 1-3substituents independently selected from C₁₋₃alkyl, CF₃, phenyl, and1,2,4-oxadiazolyl, Z¹ and Z² are each CO, —OC(O)—, —C(O)O—, or a directbond, Y is CH₂, and each W¹ is independently selected from the groupconsisting of hydrogen, halogen, and C₁₋₃alkyl, and is in a position onthe aromatic ring adjacent to the —CF₂P(O)(OH)₂ group.
 10. A compound inaccordance with claim 1, which compound is selected from the compoundsin Table 1 and Table 2, or a pharmaceutically acceptable salt or prodrugthereof: TABLE 1 Structures of Examples Example Method

1 A + C

2 B + C

3 B + D

4 A + I + D

5 A + H + D

6 B + D

7 A + D

8 B + D

9 B + D

10 B + D

11 B + D

12 A + C + F

13 A + C + G

14 A + C + F

15 A + C + G

16 A + C + G

17 A + C + G

18 A + C + G

19 A + C + G

20 A + C + G

21 A + C + G

22 A + D

23 A + D

24 A + D

TABLE 2


11. A compound in accordance with claim 1, which compound is selectedfrom the compounds listed below, or a pharmaceutically acceptable saltor prodrug thereof: Example 1:[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methylphosphonicacid; Example 2:Difluoro(4-(3-oxo-2,3-diphenylpropyl)phenyl]methylphosphonic acid;Example 3:4-[2-(Benzyloxy)-1-(methoxycarbonyl)-2-oxoethyl]phenyl(difluoro)methylphosphonic acid; Example 4:2-Bromo-4-[2-phenyl-2-(3-phenyl-1,2,4-oxadiazol-5-yl) ethyl] phenyl(difluoro)methylphosphonic acid; Example 5:2-Bromo-4-[2-phenyl-2-(5-phenyl-1,2,4-oxadiazol-3-yl)ethyl]phenyl(difluoro)methylphosphonic acid; Example 6:[4-(2-Benzotriazol-1-yl-2-m-tolylethyl)-phenyl]difluoromethylphosphonicacid; Example 7:{4-[2-Benzotriazol-1-yl-2-(4-fluorophenyl)-ethyl]-2-bromophenyl}difluoromethyl phosphonic acid; Example 8:{4-[2-Benzotriazol-1-yl-2-(4-trifluoromethylphenyl)-ethyl] phenyl}difluoromethylphosphonic acid disodium salt; Example 9:(4-2-(1H-1,2,3-Benzotriazol-1-yl)-2-[4-(methyloxycarbonyl)phenyl]ethylphenyl)(difluoro)methylphosphonic acid; Example 10:{4-[2-(1H-1,2,3-benzotriazol-1-yl)-2-(4-fluorophenyl)ethyl]phenyl}(difluoro)methylphosphonic acid; Example 11:{4-[2-(1H-1,2,3-benzotriazol-1-yl)-2-phenylethyl]phenyl}(difluoro)methylphosphonic acid; Example 12: {[(2,2-dimethylpropanoyl)oxy]methyl}hydrogen[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methylphosphonate;Example 13:Bis{[(2,2-dimethylpropanoyl)oxy]methyl}[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methylphosphonate; Example 14:1-{[[[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl)(difluoro)methyl](hydroxy)phosphoryl]oxy}-2-methylpropyl propionate; Example 15:[1-(isobutyryloxy)ethyl]hydrogen[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methylphosphonate; Example 16: Bis[(isobutyryloxy)methyl][2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methylphosphonate; Example 17: [(isobutyryloxy)methyl]hydrogen [2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methylphosphonate; Example 18:Bis{[(isopropoxycarbonyl)oxy]methyl}[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methylphosphonate; Example 19:[(isopropoxycarbonyl)oxy]methyl hydrogen[2-bromo-4-(3-oxo-2,3-diphenyl)phenyl] (difluoro) methylphosphate;Example 20:Dibenzyl[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methylphosphonate;Example 21: Benzyl hydrogen[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methylphosphonate; Example 22:[2-bromo-4-(3-oxo-2-phenylbutyl)phenyl](difluoro)methylphosphonic acid;Example 23:{2-bromo-4-[3-oxo-2-phenyl-3-(1,3-thiazol-2-yl)propyl]phenyl}(difluoro)methylphosphonic acid; and Example 24:{2-bromo-4-[2-(4-methoxy-1,3-thiazol-2-yl)-3-oxo-3-phenylpropyl)phenyl}(difluoro)methylphosphonic acid.
 12. A compound having formula Ia, or apharmaceutically acceptable salt thereof,

wherein at least one group —OG is not —OH, said group —OG being a groupthat is converted to —OH under physiological conditions during or afteradministration to a mammalian patient, thereby yielding a phosphonicacid group, or a salt thereof, wherein all substituent groups other thanG are as defined in claim
 1. 13. A compound as recited in claim 12,wherein one group G is selected from phenyl, —CHR′phenyl and—CHR′OC(═O)R″, and the second group G is independently selected from H,phenyl, —CHR′phenyl and —CHR′OC(═O)R″, wherein each R′ is H or C₁₋₆alkyland each R″ is —C₁₋₆alkyl or —OC₁₋₆alkyl, wherein C₁₋₆alkyl and—OC₁₋₆alkyl in each occurrence is optionally substituted with one ormore substituents independently selected from 1-5 halogen atoms, aphenyl group, or a mixture of these, and each phenyl group in eachoccurrence is optionally substituted with 1-3 substituents independentlyselected from halogen, —CH₃, —CF₃, —OCH₃ and —OCF₃.
 14. A compound asrecited in claim 12, wherein one substituent group G is H.
 15. Acompound as recited in claim 12, wherein the two groups G are the same.16. A pharmaceutical composition which is comprised of a compound inaccordance with claim 1 in combination with a pharmaceuticallyacceptable carrier.
 17. A pharmaceutical composition in accordance withclaim 16, further comprising a second anti-diabetic or anti-obesityeffective compound.
 18. A method of treating, controlling or preventingdiabetes and complications thereof in a mammalian patient in need ofsuch treatment comprising administering to said patient an anti-diabeticeffective amount of a compound in accordance with claim
 1. 19. A methodof treating, controlling or preventing obesity in a mammalian patient inneed of such treatment comprising administering to said patient ananti-obesity effective amount of a compound in accordance with claim 1.20. A method in accordance with claim 18, further comprisingadministering to said patient a second anti-diabetic compound or ananti-obesity compound in an amount effective to treat, control orprevent diabetes or obesity.
 21. A method in accordance with claim 19,further comprising administering to said patient a second anti-obesitycompound or an anti-diabetic compound in an amount effective to treat,control or prevent obesity or diabetes.
 22. A pharmaceutical compositionin accordance with claim 16, further comprising an HMG-CoA reductaseinhibitor.
 23. A method in accordance with claim 18, further comprisingadministering to said patient an effective amount of an HMG-CoAreductase inhibitor.
 24. A method for treating, controlling orpreventing atherosclerosis in a mammalian patient in need of suchtreatment comprising administering to said patient an effective amountof a compound of claim 1 and an effective amount of an HMG-CoA reductaseinhibitor.
 25. A method of treating, preventing, or controlling one ormore diseases or conditions selected from the group consisting of Type 1diabetes, Type 2 diabetes, inadequate glucose tolerance, insulinresistance, obesity, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, low HDL levels, atherosclerosis, vascularrestenosis, inflammatory bowel disease, pancreatitis, adipose celltumors, adipose cell carcinoma, liposarcoma, dyslipidemia, cancer, andneurodegenerative disease, said method comprising the administration ofan effective amount of the compound of claim
 1. 26. A method oftreating, preventing, or controlling one or more diseases or conditions,selected from the group consisting of Type 1 diabetes, Type 2 diabetes,inadequate glucose tolerance, insulin resistance, obesity,hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDLlevels, atherosclerosis, vascular restenosis, inflammatory boweldisease, pancreatitis, adipose cell tumors, adipose cell carcinoma,liposarcoma, dyslipidemia, cancer, and neurodegenerative disease, saidmethod comprising the administration of an effective amount of thecompound of claim 1 and the administration of an effective amount of oneor more pharmaceutically active compounds selected from the groupconsisting of an HMG-CoA reductase inhibitor, an anti-obesity agent, andan antidiabetic compound.
 27. A pharmaceutical composition for thetreatment, prevention or control of one or more diseases or conditionsselected from the group consisting of Type 1 diabetes, Type 2 diabetes,inadequate glucose tolerance, insulin resistance, obesity,hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDLlevels, atherosclerosis, vascular restenosis, inflammatory boweldisease, pancreatitis, adipose cell tumors, adipose cell carcinoma,liposarcoma, dyslipidemia, cancer, and neurodegenerative disease, saidcomposition comprising an effective amount of a compound of claim 1 anda pharmaceutically acceptable carrier.
 28. A pharmaceutical compositionfor the treatment, prevention or control of one or more diseases orconditions, selected from the group consisting of Type 1 diabetes, Type2 diabetes, inadequate glucose tolerance, insulin resistance, obesity,hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDLlevels, atherosclerosis, vascular restenosis, inflammatory bowelsyndrome, pancreatitis, adipose cell tumors, adipose cell carcinoma,liposarcoma, dyslipidemia, cancer, and neurodegenerative disease, saidcomposition comprising (1) an effective amount of the compound of claim1, (2) an effective amount of one or more pharmaceutically activecompounds selected from the group consisting of an HMG-CoA reductaseinhibitor, an anti-obesity agent, and an anti-diabetic agent, and (3) apharmaceutically acceptable carrier.
 29. A pharmaceutical compositionfor the treatment, prevention or control of one or more diseases orconditions, selected from the group consisting of Type 1 diabetes, Type2 diabetes, inadequate glucose tolerance, insulin resistance, obesity,hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDLlevels, atherosclerosis, vascular restenosis, inflammatory boweldisease, pancreatitis, adipose cell tumors, adipose cell carcinoma,liposarcoma, dyslipidemia, cancer, and neurodegenerative disease, saidcomposition comprising: (1) an effective amount of the compound of claim1, (2) an effective amount of one or pharmaceutically active compoundsselected from the group consisting of: (a) insulin sensitizers including(i) PPARγ agonists such as the glitazones (e.g. troglitazone,pioglitazone, englitazone, MCC-555, rosiglitazone, and the like), andcompounds disclosed in WO97/27857, 97/28115, 97/28137 and 97/27847; (ii)biguanides such as metformin and phenformin; (b) insulin or insulinmimetics; (c) sulfonylureas such as tolbutamide and glipizide, orrelated materials; (d) α-glucosidase inhibitors (such as acarbose); (e)cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors(lovastatin, simvastatin and pravastatin, fluvastatin, atorvastatin,rivastatin and other statins), (ii) sequestrants (cholestyramine,colestipol and a dialkylaminoalkyl derivatives of a cross-linkeddextran), (iii) nicotinyl alcohol, nicotinic acid or a salt thereof,(iv) PPARα agonists such as fenofibric acid derivatives (gemfibrozil,clofibrate, fenofibrate and benzafibrate), (v) inhibitors of cholesterolabsorption for example beta-sitosterol and (acyl CoA:cholesterolacyltransferase) inhibitors for example melinamide and (vi) probucol;(f) PPARα/γ agonists; (g) antiobesity compounds such as appetitesuppressants, fenfluramine, dexfenfluramine, phentiramine, sulbitramine,orlistat, neuropeptide Y5 inhibitors (NP Y5 receptor antagonosts),leptin, which is a peptidic hormone, β₃ adrenergic receptor agonists,and PPARγ antagonists and partial agonists; (h) ileal bile acidtransporter inhibitors; and (i) insulin receptor activators; and (3) apharmaceutically acceptable carrier.